JP3287574B2 - 2,7-substituted octahydro-1H-pyrido [1,2-A] pyrazine derivative - Google Patents

Abstract

PCT No. PCT/IB95/00689 Sec. 371 Date Mar. 26, 1997 Sec. 102(e) Date Mar. 26, 1997 PCT Filed Aug. 24, 1995 PCT Pub. No. WO96/10571 PCT Pub. Date Apr. 11, 1996Substituted pydrido[1,2-a]pyrazines of general formula I wherein Ar and Ar1 represent various carbocyclic and heterocyclic aromatic rings; A represents O, S, SO, SO2, C=O, CHOH, or -(CR3R4) and n is 0-2 as well as precursors thereto are ligands for dopamine receptor subtypes within the body and are therefore useful in the treatment of disorders of the dopamine system. <IMAGE> I

Description

The present invention relates to novel pharmacologically active 2,7-substituted octahydro-1H-pyrido [1,2-a] pyrazine derivatives, their acid addition salts, and certain classes thereof. For the precursor of The compounds of the invention, dopamine receptor subtypes in an animal body, in particular ligands for the dopamine D ₄ receptor, therefore, is effective in the treatment of disorders of the dopamine system.

BACKGROUND OF THE INVENTION Molecular biology techniques have revealed the existence of several subtypes of dopamine receptors. Dopamine D ₁ receptor subtype has been shown to occur in at least two distinct forms. D ₂ at least one form of the two forms and D ₃ receptor subtype of receptor subtype, have also been discovered. More recently, D ₄ [Van Tol et al., Nature (London), 1991, 350, 6
10] and D ₅ [Sunahara et, al., Nature (London, 1991,
350,614] receptor subtypes have been described.

The compounds according to the invention, the body of dopamine receptor subtypes, especially a ligand for dopamine D ₄ receptors, therefore, the treatment of disorders of the dopamine system, is used in the prevention and / or diagnosis.

Dopamine receptors include, but controls a large number of pharmacological events, while since all of these events is not currently known, be compounds that act on dopamine D ₄ receptors exerts wide range of therapeutic effects in animals Sex exists.

WO 94/10162 and WO 94/10145 disclose that dopamine ligands cause schizophrenia, nausea, Parkinson's disease, late dyskinesia, and extrapyramidal side effects associated with treatment with conventional neuroleptics, neuroleptic malignant syndrome, and Have been reported for use in the treatment and / or prevention of disorders of the dopamine system, including hypothalamic-pituitary dysfunction such as hyperprolactinemia and amenorrhea.

Upper gastrointestinal motility is thought to be under control of the dopamine system. The compounds according to the invention can thus be used for the prevention and / or treatment of gastrointestinal disorders and for promoting gastric emptying.

Addiction inducers such as cocaine and amphetamine have been shown to interact with the dopamine system. Compounds capable of negating this effect, including the compounds according to the invention, are therefore valuable in preventing or reducing dependence on dependence-inducing agents.

Dopamine is known to be a peripheral vasodilator; for example, it has been shown to have a dilating effect on the renal vascular bed. This implies that the compounds of the present invention are beneficial in controlling vascular blood flow.

Localization of dopamine receptor mRNA in rat heart and large blood vessels has been indicated. This suggests a role for dopamine receptor ligands in controlling cardiovascular function by affecting cardia and smooth muscle contractility or by regulating secretion of vasoactive substances. The compounds according to the invention therefore assist in preventing and / or treating conditions such as hypertension and congestive heart failure.

The presence of D ₄ receptor mRNA in rat kidney has been pointed out (Cohen, et al.Proc.Nat.Acad.Sci., 1992,89,1
2093), and dopamine and D ₄ receptors suggesting that plays a role in visual function. The compounds of the present invention are therefore effective in treating visual impairment. Furthermore, D ₄ receptors, affect the melatonin biosynthesis in children retina (chick retina) (Zawilska, Nowa
k, Neuroscience Lett., 1994, 166, 203), since melatonin is used for the treatment of sleep disorders, the compounds of the present invention are also sufficiently effective for the treatment of sleep disorders.

Salch, et al. Tetrahedron, 1994, 50, 1811 has the formula: Wherein R ₁ is H or OH, and R ₂ is 2-pyridinyl or 4-FC ₆ H ₄ CO. ] The compound represented by these is described.

Bright and Desai (US Patent No. 5,122,525, assigned to the assignee of the present application) has the formula: Wherein X is N or CH, and Y represents a certain pyrazolo, triazolo, tetrazolo or cycloimide group. ] An optically active or racemic pyrido [1,2-a] represented by
A pyrazine derivative is described. These compounds are drugs that relieve anxiety.

Godek, et al (U.S. Pat. No. 5,185,449, assigned to the assignee of the present application) is a (C ₁ -C ₃ ) alkyl-4,6 precursor to a bisaza-bicyclic anxiolytic. , 7,8,
9,9a-Hexahydro-2H, 3H-pyrido [1,2-a] pyrazin-1-one-7-carboxylate esters are described.

WO 93/25552 assigned to the assignee of the present applicant.
Are octahydro-1H-pyrido [1,2-a] pyrazinylethylcarboxamide anxiolytics; and anxiolytics (+) and (−)-3-oxo-N- [2- [7-
{2- (3- (1,2-benzisoxazolyl)}-2,
3,4,6, (7S), 8,9, (9aS) -octahydro-1H-pyrido [1,2a] pyrazinyl] -ethyl] -2-oxaspiro-
Disclosed are methods and intermediates for the synthesis of [4,4] -nonane-1-carboxamide.

WO 92/13858 assigned to the assignee of the present applicant.
Is obtained by reacting a racemic mixture with D-(-) or L-(+) tartaric acid, separating the resulting diastereomeric tartrate and converting each enantiomeric tartrate to the free base, And a method for resolving the enantiomer of 7- (hydroxymethyl) -2- (2-pyrimidinyl) -octahydro-2H-pyrido [1,2-a] pyrazine.

U.S. Pat. No. 5,326,874 has the formula: Wherein R is (C ₁ -C ₃ ) alkyl. The present invention relates to a method for producing a dialkyl trans-piperidine-2,5-dicarboxylate via a trans-substituted piperidine derivative represented by the following formula: These trans-piperidine derivatives are
Certain neuroleptic, racemic or optically active perhydro-
Particularly useful as intermediates in the synthesis of 1H-pyrido [1,2-a] pyrazines, these are described in US Pat. No. 5,157,033.
And the relative stereochemical formula described in 4: Wherein Z is H or Cl; Y is O or S; n is 1, 2, 3, or 4; L and X may be the same or different, H, alkyl, aryl, carbocyclic or heterocyclic group. ].

SUMMARY OF THE INVENTION The present invention provides a compound of the formula: Wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl; Ar ¹ is phenyl, pyridinyl , pyridazinyl, there pyrimidinyl or pyrazinyl; A is, O, S, SO, SO 2, C = O, CHOH or - (CR ³
It is R ^4); n is 0, 1 or 2; each of Ar and Ar ^1, independently, and, optionally, fluorine, chlorine, bromine, iodine, cyano, nitro, thiocyano, -SR, _{-SOR, -SO 2 R, -NHSO 2} R, - (C 1 ~C
₆ ) alkoxy, -NR ¹ R ² , -NRCOR ¹ , -CONR ¹ R ² , Ph,
_{-COR, COOR, - (C 1} ~C 6) alkyl; - from (C ₁ ~C ₆₎ alkyl ;-( C ₃ ~C ₆₎ cycloalkyl, and trifluoromethoxy substituted with 1-6 halogens Each and every R, R ¹ and R ² may be hydrogen, — (C _1-
C ₆₎ alkyl; fluorine, chlorine, substituted by 1 to 13 halogen selected from bromine and iodine - (C ₁
-C ₆₎ alkyl; phenyl, benzyl, - (C ₂ ~C ₆₎ alkenyl, - (C ₃ ~C ₆₎ cycloalkyl and - (C ₁ ~
C ₆ ) is independently selected from the group consisting of alkoxy; each and every R ³ and R ⁴ are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and i-propyl. And diastereomers and optical isomers thereof; and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention provides a method, wherein Ar is phenyl, naphthyl, benzoxazolonyl,
A is O, S, SO ₂ , C ＝ O, CHOH or CH ₂ ; n is 0 or 1; Ar and Ar ¹ are fluorine, chlorine, indolyl, indolonyl, benzimidazolyl or quinolyl; , Cyano, -NR ¹ R ² ,-
(C ₁ -C ₆ ) alkoxy, —COOR, —CONR ¹ R ² and — (C
₁ -C ₆₎ with up to three substituents independently selected from the group consisting of alkyl optionally substituted independently according compounds of the formula I and their pharmaceutically acceptable salts.

In another embodiment, the present invention relates to compounds of formula I wherein A is O or S; n is 1; and Ar is phenyl or substituted phenyl, and pharmaceutically acceptable compounds thereof. Salt.

In another aspect, the present invention, A is located in CH _2; n is located at 0; Ar is a benzoxazolone cycloalkenyl or substituted benzoxazolone alkenyl, compounds of the formula I and their Pertains to pharmaceutically acceptable salts.

In another embodiment, the present invention provides a compound of formula I, wherein A is CH ₂ ; n is 0; and Ar is indolyl or substituted indolyl.
And a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of formula I, wherein A is C = O or CHOH; n is 0 or 1; and Ar is phenyl or substituted phenyl. Pertains to chemically acceptable salts.

In another embodiment, the present invention provides a compound of formula I, wherein A is O; Ar is fluorophenyl, difluorophenyl or cyanophenyl; and Ar ¹ is chloropyridinyl. Permissible salts.

In another embodiment, the present invention relates to a compound of formula I, wherein A is O; Ar is fluorophenyl, difluorophenyl or cyanophenyl; and Ar ¹ is fluoropyrimidinyl; Pertains to chemically acceptable salts.

In another embodiment, the present invention provides a compound of formula I, wherein A is O; Ar is fluorophenyl, difluorophenyl or cyanophenyl; and Ar ¹ is fluorophenyl. Pertains to chemically acceptable salts.

In another aspect, the invention, Ar ¹ is 5-chloro - pyridin-2-yl, the compounds of the formula I and according to a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method, wherein Ar ¹ is 5-fluoro-pyrimidin-2-yl.
Includes compounds of Formula I and pharmaceutically acceptable salts.

 In a preferred embodiment of the present invention, A is O.

In another aspect of the present invention, A, S, SO or SO _2.

In another embodiment of the present invention, A is C = O or CHOH.

In another preferred embodiment of the invention, A is CH
₂

In another preferred embodiment of the invention, Ar is phenyl or substituted phenyl.

In another preferred embodiment of the invention, Ar is naphthyl or substituted naphthyl.

In another preferred embodiment of the invention, Ar is benzoxazolonyl or substituted benzoxazolonyl.

In another preferred embodiment of the invention, Ar is indolyl or substituted indolyl.

In another preferred embodiment of the invention, Ar is indolonyl or substituted indolonyl.

In another preferred embodiment of the invention, Ar is benzimidazolyl or substituted benzimidazolyl.

In another preferred embodiment of the invention, Ar is quinolyl or substituted quinolyl.

In another preferred embodiment of the invention, Ar ¹ is
Phenyl or substituted phenyl.

In another preferred embodiment of the invention, Ar ¹ is
Pyridinyl or substituted pyridinyl.

In another preferred embodiment of the invention, Ar ¹ is
Pyridazinyl or substituted pyridazinyl.

In another preferred embodiment of the invention, Ar ¹ is
Pyrimidinyl or substituted pyrimidinyl.

In another preferred embodiment of the invention, Ar ¹ is
Pyrazinyl or substituted pyrazinyl.

A preferred compound of the present invention is: (7R, 9aS) -7- (4-fluorophenoxy) methyl-
2- (5-chloro-pyridin-2-yl) -2,3,4,6,7,
8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7R, 9aS) -7- (3,5-difluorophenoxy) methyl-2- (5-chloro-pyridin-2-yl ) −2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; 3-[(7R, 9aS) -2- (5-chloro-pyridine-2-
Yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazin-7-ylmethyl] -3H-benzoxazol-2-one; 3- [ (7R, 9aS) -2- (5-fluoro-pyrimidine-
(2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazin-7-ylmethyl] -3H-benzoxazol-2-one; 7R, 9aS) -7- (4-Fluorophenoxy) methyl-
2- (5-fluoro-pyrimidin-2-yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7R, 9aS) -7- (3,5-difluorophenoxy) methyl-2- (5-fluoro-pyrimidine -2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine; (7R, 9aS) -7- (3,4-difluorophenoxy) methyl-2- (5-fluoro-pyrimidin-2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine; (7R, 9aS) -7- (3-cyanophenoxy) methyl-2
-(5-fluoro-pyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7R, 9aS) -7- (4-cyanophenoxy) methyl-2
-(5-fluoro-pyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7R, 9aS) -7- (4-iodophenoxy) methyl-2
-(5-fluoro-pyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7R, 9aS) -7- (4-fluorophenoxy) methyl-
2- (4-fluorophenyl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (4- Fluorophenoxy) methyl-
2- (5-fluoro-pyrimidin-2-yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (2-carbomethoxy-4-fluorophenoxy) methyl-2- (5- Fluoro-pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-
Pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (2-bromo-4-fluorophenoxy) methyl-2- (5-fluoro-pyrimidin-2-yl) -2,3,4, 6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (4-fluoro-2-trifluoromethylphenoxy) methyl-2- (5 -Fluoro-pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-
1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (3,5-difluorophenoxy) methyl-2- (5-chloro-pyridin-2-yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (4-fluorophenoxy) methyl-
2- (5-chloro-pyridin-2-yl) -2,3,4,6,7,
8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (4-fluoro-2-methylphenoxy) methyl-2- (5-fluoro-pyrimidine-2 -Yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (2,4-difluorophenoxy) Methyl-2- (5-fluoro-pyrimidin-2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine; (7S, 9aS) -7- (3-methyl-phenoxy) methyl-
2- (5-fluoro-pyrimidin-2-yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (3,4-difluorophenoxy) methyl-2- (5-fluoro-pyrimidine -2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine; (7S, 9aS) -7- (3,5-difluoro-phenoxy) methyl-2- (5-fluoropyrimidin-2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine; (7S, 9aS) -7- (3-cyano-phenoxy) methyl-
2- (5-fluoropyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (3-trifluoromethyl-phenoxy) methyl-2- (5-fluoropyrimidine-2 -Yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (4-trifluoromethyl-phenoxy) ) Methyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS ) -7- (3-Trifluoromethoxy-phenoxy) methyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [ (7,9aS) -7- (3-methoxy-phenoxy) methyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (4-methoxy-phenoxy) methyl-2- (5-fluoropyrimidine-2 -Yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; and pharmaceutically acceptable salts thereof.

The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of formula I. The compounds of the formula I are basic in nature and are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of these compounds of Formula I are those that are capable of forming non-toxic acid addition salts, i.e., hydrochloric acid Salt, bromate, iodate, nitrate, sulfate,
Bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate,
Pharmaceuticals such as ascorbate, succinate, maleate, fumarate, gluconate, glucanoate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate Are salts containing anions that are acceptable to the

As used herein, the term "one or more substituents" refers to one or more of the possible substituents based on the number of available sites.
Including the maximum number.

Those of ordinary skill in the art will recognize that certain combinations of substituents are chemically unstable, and avoid such combinations or protect sensitive groups with known protecting groups. Will do.

The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon groups having straight, branched or cyclic sites or combinations thereof.

The term “alkoxy” as used herein, unless otherwise indicated, refers to a group having the formula —O-alkyl, where “alkyl” is as defined above.

The compound of formula I contains a chiral center,
Thus, they exist in different enantiomeric forms. The present invention relates to all optical isomers and all other stereoisomers of the compounds of formula I and mixtures thereof.

The compounds according to the invention, the body of dopamine receptor subtypes, especially a ligand for dopamine D ₄ receptors, therefore, the treatment of disorders of the dopamine system, is used for the prevention or diagnosis.

It is a generally accepted knowledge that dopamine receptors are important for many functions in animals. For example, the altered function of these receptors is
It is involved in the development of mental illness, addiction, sleep, nutrition, learning, memory, sex behavior and blood pressure.

The present invention relates to schizophrenia, nausea, Parkinson's disease, late dyskinesias and extrapyramidal side effects associated with treatment with conventional psycholeptic drugs, malignant syndromes of neuroleptic and visual disorders such as hyperprolactinemia and amenorrhea. Provided are dopamine ligands for use in the treatment and / or prevention of disorders of the dopamine system, including disorders of hypothalamic pituitary function.

Upper gastrointestinal motility is thought to be under control of the dopamine system. The compounds according to the invention are used for the prevention or treatment of gastrointestinal disorders as well as for promoting gastric emptying.

Addiction inducers such as cocaine and amphetamine have been shown to interact with the dopamine system. Compounds that can abolish this potency, including those according to the present invention, are therefore valuable in preventing or reducing dependence on dependence-inducing agents.

Dopamine is known as a peripheral vasodilator; for example, it has been shown to exert a dilating effect on the renal vascular bed. This indicates that the compounds of the present invention are beneficial in controlling vascular blood flow.

Localization of dopamine receptor mRNA in rat heart and large blood vessels has been indicated. This suggests a role for dopamine receptor ligands in controlling cardiovascular function by affecting cardia and smooth muscle contractility or by modulating the secretion of vasoactive substances. The compounds according to the invention assist in preventing and / or treating conditions such as hypertension and congestive heart failure.

The presence of D ₄ receptor mRNA in rat retina has been noted (Cohen, et al. Proc.Nat.Acad.Sci. , 1992,8
9,12093), suggesting that dopamine and D ₄ receptors play a role in visual function. The compounds of the present invention are therefore effective in treating visual impairment. Furthermore, D ₄ receptors, affect the melatonin biosynthesis in children retina (Zawilska, Nowak, Neuroscience Le
tt., 1994, 166, 203), since melatonin has been used to treat sleep disorders, the compounds of the present invention are also effective for treating sleep disorders satisfactorily.

The present invention also relates to a pharmaceutical composition for treating or preventing a disease or condition whose treatment or prevention is effected or promoted by altering dopamine-mediated neurotransmission in a mammal, comprising the steps of: 4. A composition comprising a potent dopaminergic effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention also provides a method for treating or preventing a disease or condition whose treatment or prevention is effected or promoted by altering dopamine-mediated neurotransmission in a mammal, the method comprising: 2. A method comprising administering an effective amount of a dopaminergic compound of claim 1 or a pharmaceutically acceptable salt thereof.

The present invention also relates to a pharmaceutical composition for treating or preventing a disease or condition whose treatment or prevention is effected or promoted by altering dopamine-mediated neurotransmission in a mammal, comprising the steps of: according to a composition comprising a compound or D ₄ receptor binding effective amount of a pharmaceutically acceptable salt thereof according to item 1, and a pharmaceutically acceptable carrier.

The present invention also provides a method for treating or preventing a disease or condition whose treatment or prevention is effected or promoted by altering dopamine-mediated neurotransmission in a mammal, the method comprising: according to a method comprising administering a compound or D ₄ receptor binding effective amount of a pharmaceutically acceptable salt thereof according to item 1.

The present invention also provides a pharmaceutical composition for treating or preventing a disease or condition whose treatment or prevention is effected or promoted by altering dopamine-mediated neurotransmission in a mammal, the method comprising: Claims 1 to 5 in amounts effective to treat or prevent such conditions.
Or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating or preventing a disease or condition whose treatment or prevention is effected or promoted by altering dopamine-mediated neurotransmission in a mammal, wherein said mammal has such a condition. Or a pharmaceutically acceptable salt thereof, in an amount effective to treat or prevent the compound of claim 1.

The invention also relates to the use of the compounds of the formula I for the treatment, prevention or diagnosis of mental disorders such as emotional psychiatric disorders, schizophrenia and schizophrenic disorder.

The present invention also provides extrapyramidal side effects of neuroleptics,
Malignant neuroleptic syndrome, late dyskinesia or Giles de La Tourettes syndr
ome), the use of a compound of formula I for the treatment, prevention or diagnosis of movement disorders.

The invention also relates to the use of a compound of formula I for the treatment, prevention or diagnosis of movement disorders such as Parkinson's disease or Huntington's disease.

The invention also relates to the treatment of gastrointestinal disorders such as gastric acid secretion,
It relates to the use of a compound of formula I for prevention or diagnosis.

The present invention also relates to the use of a compound of formula I for the treatment, prevention or diagnosis of gastrointestinal disorders such as vomiting.

The invention also relates to the use of a compound of formula I for the treatment, prevention or diagnosis of substance abuse, drug dependence or substance abuse.

The invention also relates to the use of a compound of formula I for the treatment, prevention or diagnosis of vascular and cardiovascular disorders such as congestive heart failure and hypertension.

The invention also relates to the use of a compound of formula I for the treatment, prevention or diagnosis of visual impairment.

The present invention also relates to the use of a compound of formula I for the treatment, prevention or diagnosis of sleep disorders.

As used herein, the term "dopaminergic effective amount" refers to a compound sufficient to inhibit dopamine binding to a dopamine receptor that has the effect of altering (ie, increasing or decreasing) dopamine-mediated neurotransmission. Means the amount of

As used herein, the term "D ₄ receptor binding effective amount", changing the dopamine mediated neurotransmission (i.e., reduce or increase) dopamine having an effect
It refers to that amount of the compound sufficient to inhibit dopamine binding to D ₄ receptors.

In another embodiment, the present invention provides a compound of formula I useful for the preparation of a compound of formula I: Wherein Ar ¹ is 5-fluoropyrimidin-2-yl or 5-chloropyridin-2-yl, and Ar is 4-
It is fluorophenyl. And an optical isomer and a stereoisomer thereof.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula I are readily prepared by several methods summarized in Schemes IX.

Although the entire route and various intermediates in Schemes IX are novel, the individual chemical steps are generally similar to known chemical transformations. Generally, suitable conditions are found in the prior art. The isolation and production of the product
This is accomplished by standard procedures known to chemists of ordinary skill. Particularly suitable conditions are exemplified below.

Intermediates known from the prior art are provided in Table I. Some intermediate enantiomers can be prepared using standard methods known to chemists of ordinary skill.

As used hereinafter, the expression "reactive inert solvent" refers to a solvent system whose components do not interact with the starting materials, reagents, or product intermediates so as not to adversely affect the yield of the desired product. Say.

During the following synthetic procedures, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This is TWGreene, Protect
ive Groups in Organic Chemistry, John Willey & Son
s, 1981; and TWGreene and PGMWuts, Protectiv
e Groups in Organic Chemistry, John Willey & Sons,
This can be achieved with conventional protecting groups such as those described in 1991.

The expression "nitrogen protecting group" used hereinafter is
A moiety that, when combined with a basic nitrogen, remains inert while other reactions are performed. The nitrogen protecting group is then removed under mild conditions, producing a free amino group. The present invention contemplates two types of nitrogen protecting groups: those that are removed by treatment with strong acids and those that are removed by hydrogenolysis.

Examples of nitrogen protecting groups that are removed by strong acids are t-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsilylethoxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, diphenylmethoxycarbonyl, trityl, acetyl and benzoyl. Is t-butoxycarbonyl (BOC).

Examples of nitrogen protecting groups that are removed by hydrogenolysis are
Benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2-phenylethyloxycarbonyl, benzyl, p-methoxybenzyloxycarbonyl and p-nitrobenzyloxycarbonyl. A preferred group is benzyloxycarbonyl.

Removal of the BOC protecting group from compounds II or V (Scheme I) can be carried out in a reaction inert solvent such as ethyl acetate, ether or chloroform with HCl gas under anhydrous conditions. Alternatively, BOC groups can be removed in aqueous solution with a strong acid such as hydrochloric acid or trifluoroacetic acid. The temperature of these reactions is not critical and it has proven convenient to carry out the reactions at ambient temperature.

Amines of Formula III or Formula VI are described by Bright and
Using methods directly analogous to those described by Desai (US Pat. No. 5,122,525), they are combined with the activated form of Ar ¹ (Scheme I) to form compounds IV or I, respectively. The term “activated form of Ar ¹ ” has the formula: [Wherein, L is a leaving group. ] Means a chemical derivative represented by “Leaving group”
The term (L) refers to a group that can be replaced by another group under appropriate conditions, including, for example, halogen, lower-alkylsulfonyl, and arylsulfonyl. The activated form of Ar ¹ also has an electron withdrawing group (E
WG) and a leaving group (L) in the ortho- or para-position to each other. When the activated form of Ar ¹ is a derivative of benzene, halogens, especially fluorine, are preferred leaving groups, and nitro or cyano are examples of preferred electron withdrawing groups. The reaction is conveniently carried out in a reaction inert solvent such as water, lower alcohols or dimethylsulfoxide at a temperature of about
It is carried out at 30 ° C to about 170 ° C. The presence of an acid acceptor, such as a trialkylamine or alkali carbonate, is effective.

Compounds IV or I are also available from Wyberg et al. (J. Org. C
hem. 1993, 58, 5101) and an activated form of Ar ¹ wherein the leaving group (L) is lower alkoxy or aryloxy, and a compound of formula III or IV Can be produced by coupling, respectively. Amines III or VI
Are reacted with a strong hydrogen atom acceptor, such as butyllithium, in a relatively inert ether solvent, preferably a relatively polar ether such as tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane. The conversion to the amide is followed by the addition of the activated form of Ar ^{1 wherein} the leaving group (L) is lower alkoxy or aryloxy. The formation of the alkali amide in the first step is carried out at a temperature of about -70 ° C to about 10 ° C, and the addition of the activated form of Ar ¹ in the second step is conveniently carried out at a temperature of about 20 ° C.
Performed at ~ 100 ° C.

Coupling alcohols of the formula II or IV with phenols of the formula ArOH,
An effective method for preparing compound V or I is to convert the alcohol moiety of compound II or IV to a leaving group, such as a lower alkylsulfonyl ester or an arylsulfonyl ester, as the first step in a two-step process. including. Alkyl- or arylsulfonyl esters are
It is prepared by reacting an alkyl- or arylsulfonyl chloride with an alcohol II or IV in the presence of a trialkylamine in a reaction inert solvent (e.g., methylene chloride) at a temperature of about -10C to about 60C. In the second step, ArOH is reacted with a suitable hydrogen atom acceptor, preferably an alkali metal hydride with an alkali metal hydride (ArO
MOM) and the alkali salt ArOM is then converted to a polar reaction inert solvent such as dimethylformamide (DMF) or dimethylsulfoxide (DMSO) at a temperature of about 0 ° C. to about
It is reacted at 150 ° C. with an alkyl- or arylsulfonyl derivative. By substituting the aromatic heterocycle with a moderately acidic NH substituent, such as 5-fluoroindole or 5-chloro-2-methylbenzimidazole, for the phenol ArOH in the second step, It can be used to prepare examples of compound I where Ar is 5-fluoroindol-1-yl or 5-chloro-2-methylbenzimidazol-1-yl. In addition, indoles such as 5-fluoroindole can be used in combination with an alkylmagnesium halide as a hydrogen atom acceptor in the second step, for example, ethylmagnesium bromide, where Ar is 5-fluoroindole-3-.
Can be used to prepare an example of a compound I that is yl (Scheme X).

Compounds of formula V or formula I can also be prepared in approximately equimolar amounts of alcohols II or IV, phenol ArOH or thiol ArSH, triarylphosphine [eg triphenylphosphine (Ph ₃ P)] and dialkylazodicarboxy. The rate [e.g., diethyl azodicarboxylate (DEAD)] in a relatively polar ethereal solvent such as tetrahydrofuran (THF), 1,4-dioxane or 1,2-dimethoxyethane at a temperature of about 0C to about 100C. It can be manufactured by combining with.

Examples of compound I wherein A is CHOH and n is 0 are prepared in a reaction inert solvent such as methylene chloride at a temperature of about -80 ° C.
At about −40 ° C., it can be prepared by converting the alcohol function of compound IV to an aldehyde of formula VII by the reaction of a mild oxidant such as dimethylsulfoxide / oxalyl chloride (Scheme II). In the second step, the aldehyde VII is then treated with an aryl metal derivative such as phenylmagnesium halide in a reaction inert solvent, preferably ether, to give compound I wherein A is CHOH and n is 0. Generate. Compounds of the formula (I) in which A is CHOH can be converted by the action of an oxidizing agent into compounds of the formula I in which A is C = O. I (A is CHOH
Many commonly known oxidants are suitable for the conversion of) to I (A is C = O), one preferred being in a reaction inert solvent such as methylene chloride at a temperature of Combination of dimethyl sulfoxide and oxalyl chloride at about -80 ° C to about -40 ° C.

A is C = O and n is 1 or A is CH
An example of a compound I wherein OH is n and n is 1 is obtained by converting the alcohol moiety of compound IV to a leaving group, such as a lower alkylsulfonyl ester or an arylsulfonyl ester, as in the first step. It can be prepared by converting the alcohol function of compound IV to a nitrile of formula VIII (Scheme III). The alkyl- or arylsulfonyl ester is reacted in a reaction inert solvent (e.g., methylene chloride) at a temperature of about -10C to about
At 60 ° C., in the presence of a trialkylamine, the alcohol IV of an alkyl- or arylsulfonyl chloride
It is produced by the reaction with In the second step, the alkyl- or arylsulfonyl ester is converted to a polar reaction inert solvent such as dimethylformamide (DMF)
Or, in dimethyl sulfoxide (DMSO), at a temperature of about 0 ° C
At about 150 ° C., treatment with alkali cyanide gives the nitrile VIII.

The nitrile VIII is an aryl metal derivative in a reaction inert solvent, preferably ether, at a temperature of about 0 ° C to about 150 ° C,
For example, treatment with phenylmagnesium halide and cuprous halide, followed by a strong acid such as aqueous sulfuric acid,
Hydrolysis at a temperature of about 20 ° C. to about 120 ° C. can provide compounds I where A is C ＝ O and n is 1 (Scheme III).

Nitrile VIII can be treated with a hydride reducing agent, such as diisobutylaluminum hydride, to produce aldehyde IX (Scheme III). Aldehyde IX is then treated with an aryl metal, such as phenylmagnesium halide, in a reaction inert solvent, preferably ether, at a temperature of about -70 ° C to about 50 ° C, so that A is CH 2
OH and n can be 1 (Scheme III).

Compounds of the formula I wherein A is O and n is 0 are described in Compernolle et al. (J. Org. Chem., 1991, 56, 5192).
X synthesized according to the method described by
And can be produced in several steps (Scheme
IV). Compound X was obtained from Bright and Desai (US Pat. No. 5,122,
By using methods analogous to those described by 525) form Compound X of the activated Ar ^1,
For example, 2-chloropyrimidine, an alkali carbonate and a reaction inert solvent such as water, at a temperature of about 25 ° C to about 150 ° C.
Can be converted to a compound of the formula XI. Removal of the ethylene ketal protecting group
According to standard conditions, it is preferably achieved in another step with a strong acid in a solvent, for example water, to produce ketone XII. Reduction of ketone XII to alcohol XIII can be accomplished in another step by reaction of aluminum or boron with a hydride reducing agent in a reaction inert solvent, many suitable examples of which are known in the literature . Sodium borohydride is a preferred example, whether used alone or supported on a reaction inert substance such as alumina in a polar protic solvent such as a lower alcohol. Substantially equimolar amounts of alcohol XIII and phenol ArOH, triarylphosphine [eg, triphenylphosphine (Ph ₃ P)], and dialkyl azodicarboxylates [eg, diethyl azodicarboxylate (DEAD)] Combining in a polar ethereal solvent such as tetrahydrofuran (THF), 1,4-dioxane or 1,2-dimethoxyethane at a temperature of about 0 ° C. to about 100 ° C., where A is O and n is 0 An effective method for preparing compounds of formula I (Scheme IV).

Some examples of compound I can be converted to other examples of compound I via reaction of their functional groups.

For example, Compound I wherein Ar ¹ is 5-fluoro-2-pyridinyl can be prepared by reacting Compound I wherein Ar ¹ is 5-bromo-2-pyridinyl in a reaction inert solvent, preferably an ether such as THF at a temperature of about 1: 1. At -120 ° C to about 0 ° C, subject to conditions sufficient to exchange bromine with a metal atom, eg, butyllithium, followed by an electrophilic fluorine source, eg, N-fluorobis (benzenesulfonamide). It can be prepared by addition (Scheme V).

Compounds I in which Ar or Ar ¹ has a chlorine, bromine or iodine substituent can be converted to analogous compounds I in which the chlorine, bromine or iodine atoms have been exchanged for hydrogen isotopes.
For example, a mixture of a compound I in which Ar ¹ is 6-chloro-3-pyridazinyl and a noble metal catalyst, for example, palladium on activated carbon, in a lower alcohol solvent under a hydrogen gas atmosphere at 1 to 10 atmospheres has Ar ¹ of 3 Produce compound I which is a pyridazinyl (Scheme VI). Similar treatment of compound I where Ar ¹ is 2-chloro-4-pyrimidinyl gives compound I where Ar ¹ is 4-pyrimidinyl.

Compound I wherein A is S is a reaction inert solvent, for example,
A in methylene chloride at a temperature of about −10 ° C. to about 50 ° C. with an oxidizing agent, such as m-chloroperbenzoic acid, results in A
₂ can be converted to compound I (Scheme VI
I).

Compound I wherein Ar ¹ has an amino substituent can be converted to an analogous compound I in which the amino substituent is replaced by a hydride. For example, a mixture of Compound I where Ar ¹ is 4-aminophenyl with isoamyl nitrite and THF at a temperature of about 25 ° C. to about 125 ° C. gives Compound I where Ar ¹ is phenyl (Scheme VIII). A similar treatment of compound I where Ar ¹ is 2-amino-4-fluorophenyl gives compound I where Ar ¹ is 4-fluorophenyl (Scheme IX).

The novel compounds of formula I and their pharmaceutically acceptable salts (the "therapeutic compounds of the invention" herein) are effective as dopaminergic agents;
That is, they have the ability to alter dopamine-mediated neurotransmission in mammals, including humans. They therefore indicate that the treatment or prevention is effected or promoted by increasing or decreasing dopamine-mediated neurotransmission,
It can function as a therapeutic agent for treating various conditions in mammals.

Compounds of the formula I, which are basic in nature, are capable of forming a wide variety of different salts with various inorganic and organic acids. Such salts need to be pharmaceutically acceptable for administration to animals, but in practice, the compounds of formula I may be initially expressed as a more pharmaceutically unacceptable salt than the reaction mixture. It is often desirable to convert the latter back to the free base compound by release and then treatment with an alkaline reagent, followed by conversion of the latter free base to a pharmaceutically acceptable acid addition salt.
The acid addition salts of the base compounds of the present invention are readily prepared by treating the base compound with a substantially equivalent amount of the selected inorganic or organic acid in an aqueous solvent medium or a suitable organic solvent, such as methanol or ethanol. It is manufactured in. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding a suitable inorganic or organic acid to the solution.

The therapeutic compounds of the invention can be administered orally, dermally (eg, through the use of a patch), parenterally, or topically. Oral administration is preferred. Generally, these compounds will most desirably contain from about 0.1 mg to about 1,0 mg / day of the dosage.
In the range of 00mg or less, or in some cases per day
Dosages from 1 mg to 1,000 mg will vary depending on the weight and condition of the individual being treated and the particular route of administration chosen. In some cases, dosage levels below the lower end of the above ranges may be rather appropriate; in other cases, higher doses may be used without adverse side effects, However, such higher doses are first divided into several smaller doses to be administered over the day.

The therapeutic compounds of the invention can be administered alone or in combination with a pharmaceutically acceptable carrier or diluent, by either of the two routes set forth above, and such administration It can be done in single or multiple doses. More specifically, the novel therapeutic compounds of the present invention can be administered in a wide variety of different dosage forms, i.e., they include various pharmaceutically acceptable inert carriers and tablets, capsules, lozenges Troches, hard candies, powders, sprays, creams, ointments, suppositories, jellies, gels, pastes, lotions, ointments, elixirs, syrups and the like. Such carriers include, for example, solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. Further, the oral pharmaceutical composition may be suitably sweetened and / or aromatized.

For oral administration, tablets containing various excipients, such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate, and glycine, may contain various disintegrants, such as starch (and preferably Can be used in conjunction with granule binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia, together with corn, potato or tapioca starch), alginic acid and certain complex silicates. Additionally,
Lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very effective for tableting purposes. Solid compositions of the same type can also be used as fillers in gelatin capsules; preferred materials in this connection include lactose,
Or lactose and high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient can be combined with various sweetening or flavoring agents, coloring substances or dyes, and if so desired. , Emulsifiers and / or suspending agents are also used in combination with diluents, such as water, ethanol, propylene glycol, glycerin and various similar combinations thereof.

For parenteral administration, solutions of a compound of the present invention in sesame or peanut oil or in aqueous propylene glycol may also be employed. Aqueous solutions must be suitably buffered, if necessary, and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for indirect, intramuscular and subcutaneous injection purposes. The preparation of all of these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques known to those skilled in the art.

In addition, when treating inflammatory conditions of the skin, it is also possible to administer the compounds of the invention locally, preferably in accordance with standard pharmacopeias, creams, jellies, gels,
It can be performed with a paste, an ointment or the like.

Dopaminergic activity relates ability of a compound to bind to a mammalian dopamine receptor, ^[3 H] for the human dopamine D ₄ receptor subtypes expressed in clonal cell line - relative ability of compounds of spiperone binding suppressing the present invention Was measured using the following procedure.

D ₄ measurement of receptor binding ability, Van Tol et al., Nat
ure (London), 1991, 350, 610.
Clonal cell line expressing the human dopamine D ₄ receptors are harvested, EDTA in 5 mM, 1.5 mM calcium chloride (CaCl _2), magnesium chloride 5mM (MgCl _2), 5mM potassium chloride and 120mM sodium chloride (NaCl ) Is homogenized (polytron) in 50 mM Tris: HCl (pH 7.4 at 4 ° C.) buffer. 48,000g of homogenate
And centrifuged for 10-15 minutes at a concentration of 150.
Resuspend in buffer at ~ 250 mg / ml. For saturation experiments, 0.75 ml aliquots of tissue homogenate, ^[3 H] -
Increase the concentration of spiperone (70.3 Ci / mmol; 10-3,000p
M final concentration), in a total volume of 1 ml, in triplicate at a temperature of 22 ° C. for 30-120 minutes. For competition binding experiments, to start the analysis by adding a membrane of 0.75 ml, indicated concentrations of competing ligands (10 ^-14 ~10 ^-3 M) and / or ^[3 H] - spiperone (100～300PM ), At a temperature of 22 ° C,
Incubate in duplicate for 60-120 minutes. Analysis of Bra
Terminating by passing quickly through the ndell cell harvester, the filter was subsequently filtered by Sunahara, RK et al.,
Tritium is monitored as described by Nature (London), 1990, 346,76. For all experiments, specific [ ³ H] -spiperone binding is defined as being suppressed by 1-10 mM (+) butaclamol. The binding data is analyzed by non-linear least squares curve fit.

The following examples are provided solely by way of example and do not limit the invention, which is defined by the appended claims.

Example 1 (7R, 9aS) -7- (phenoxy) methyl- (2-pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-
1H-pyrido [1,2-a] pyrazine 0.385 g (1.55 mmol) of (7R, 9aS) -7-hydroxymethyl- (2-pyrimidin-2-yl) -2,3,4,6,7,8,9,
9a-octahydro-1H-pyrido [1,2-a] pyrazine (Preparation Example 4), 0.220 g (2.34 mmol) of phenol and
A solution of 0.488 g (1.86 mmol) of triphenylphosphine in 30 mL of dry THF was treated with 0.324 g (1.86 mmol) of diethyl azodicarboxylate and the mixture was stirred at 23 ° C. for 16 hours. Evaporate the solvent, dissolve the residue in ethyl ether,
Treated with HCl (g) in ether. The precipitate was collected on a Buchner funnel and washed three times with 1: 1 ether: ethyl acetate. The solid was dissolved in water, made basic with 1 M NaOH and extracted with chloroform. The organic layer was washed with 1M NaOH (2x) and water (1x), dried (magnesium sulfate),
And evaporated to give 0.310 g of (7R, 9aS) -7-phenoxymethyl-2,3,4,6,7,8,9,9a-octahydro- (2-
Pyrimidin-2-yl) -1H-pyrido [1,2-a] pyrazine was provided. mp (.HCl) 203-205 ° C. ¹³ C NMR (base, CDCl ₃ ): δ 27.0, 29.0, 36.4, 43.6, 49.1, 54.9, 58.8, 6
0.8,70.9,109.8,114.5,120.6,129.4,157.7,159.0,161.
Five. HRMS Calcd for _{C 19 H 24 N 4 O:} 324.195; Found: 324.
194.

Example 2 7- (Substituted-phenoxy) methyl- (2-pyrimidine-
2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazines The compound represented by the above formula was replaced with an appropriate phenol and, according to Example 1, 7-hydroxymethyl- (2-
Isomerism of pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2a] pyrazine (Preparation Example 4, US Pat. Nos. 5,122,525 and WO 92/13858) Manufactured from body. Purification is generally achieved by flash silica gel chromatography using a mixture of ethyl acetate and hexane or a mixture of chloroform and methanol as the eluting solvent. Stereochemical configuration, 7-
Figure 3 shows the (optionally substituted phenoxy) methyl substituent, melting point and high resolution mass spectrum (HRMS) data for monohydrochloride.

Example 2a (7SR, 9aSR) -7-phenoxymethyl: mp 119-122 ° C; C
Anal calculated value for ₁₉ H ₂₄ N ₄ OHCl: C, 63.23; H, 6.98; N, 1
5.53; Found: C, 63.19; H, 7.30; N, 15.56.

Example 2b (7R, 9aR) -7-phenoxymethyl: mp 226-231 ° C .; C ₁₉ H
HRMS calcd for ₂₄ N ₄ O: 324.1945; Found: 324.1920.

Example 2c (7RS, 9aSR) -7- ( 4- fluorophenoxy) _{methyl: mp263~266 ℃; C 19 H 23} FN 4 HRMS calcd for O: 342.1
851; Found: 342.1796.

Example 2d (7RS, 9aSR) -7-｛(2,4-difluoro) phenoxymethyl): mp 242.5-244 ° C .; HRMS calculated for C ₁₉ H ₂₂ F ₂ N ₄ O: 360.1762; found: 360.1775 .

Example 2e (7RS, 9aSR) -7- ( 3,4- difluorophenoxy) _{methyl: mp239~240 ℃; C 19 H 22} F 2 N 4 HRMS calcd for O: 36
0.1762; found: 360.1745.

Example 2f (7RS, 9aSR) -7-{(3-fluoro) phenoxy} methyl: mp 242 ° -243 ° C .; HRMS calculated for C ₁₉ H ₂₃ FN ₄ O: 34.
2.1856; found: 342.11851.

Example 2g (7RS, 9aSR) -7- (2-naphthoxymethyl): mp143-
145 ° C .; HRMS calculated for C ₂₃ H ₂₆ N ₄ O: 374.2107; found:
374.2097.

Example 2h (7RS, 9aSR) -7- (1-naphthoxymethyl): mp243-
245 ° C; HRMS calculated for C ₂₃ H ₂₆ N ₄ O: 374.2107; found:
374.2098.

Example 2i (7RS, 9aSR) -7- (4-fluoro-3-methylphenoxy) methyl: mp 232 ° -233 ° C .; HRMS for C ₂₀ H ₂₅ FN ₄ O:
Calculated: 356.2012; Found: 356.1992.

Example 2j (7RS, 9aSR) -7-{(3-carbomethoxy) phenoxymethyl}: mp 194-196 ° C; HRMS calcd for C ₂₁ H ₂₆ N ₄ O ₃ : 382.2005; found 382.2010.

Example 2k (7RS, 9aSR) -7- ( 5- fluoro-8-yloxy) _{methyl: mp218~220 ℃; C 22 H 25} FN 5 HRMS calcd for O (MH +): 394.2043; Found: 394.2059.

Example 2l (7RS, 9aSR) -7 - [{(2- methoxy-5- (1-methyl) ethyl} phenoxy]: mp94~99 ℃; C ₂₃ H ₃₂
HRMS calcd for N ₄ O _2: 396.2518; Found: 396.2504.

Example 2m (7RS, 9aSR) -7 - [{(2- methoxy-3- (1-methyl) ethyl} phenoxy]: mp219~221 ℃; C ₂₃ H
₃₂ HRMS calcd for N ₄ O _2: 396.2518; Found: 396.252
2.

Example 2n (7RS, 9aSR) -7 - [(2- methoxy-4-acetyl)] phenoxymethyl: mp224 ℃ _{(decomposition); C 22 H 28 N 4} O 3
HRMS calc for: 396.215; found: 396.210.

Example 2o (7R, 9aS) -7- { 3- (1- methyl) ethylphenoxy} methyl: mp70~120 ℃ _{(decomposition); C 22 H 30 N 4} HR for O
MS calculated: 366.2413; found: 366.2420.

Example 2p (7R, 9aS) -7 - {(2- methoxy) phenoxy} methyl: mp213~215 ℃; HRMS calcd for _{C 20 H 26 N 4 O 2} : 354.2
050; found: 354.2209.

Example 2q (7R, 9aS) -7-{(4-acetamido) phenoxy}
Methyl: mp 192 ° C; HRMS calculated for C ₂₁ H ₂₇ N ₅ O ₂ : 381.21.
59; Found: 381.2120.

Example 2r (7R, 9aS) -7- {4- (1,1-dimethyl) ethyl-phenoxy} methyl: mp 237-244 ° C. (decomposition); HRMS calculated for C ₂₃ H ₃₂ N ₄ O: 380.2576; measurement Value: 380.2674.

Example 2s (7R, 9aS) -7- {3- (1,1-dimethyl) ethyl-phenoxy} methyl: mp 229-230 ° C. (decomposition); HRMS calculated for C ₂₃ H ₃₂ N ₄ O: 380.2576; measurement. Value: 380.2577.

Example 2t (7R, 9aS) -7- {2- (1,1-dimethyl) ethyl-phenoxy} methyl: mp 240-241 ° C .; HRM against C ₂₃ H ₃₂ N ₄ O
S Calculated: 380.2576; Found: 380.2580.

Example 2u (7R, 9aS) -7- ( 4- methoxy - phenoxy) methyl: mp219~222 ℃; HRMS calcd for _{C 20 H 26 N 4 O 2} : 354.2
050; found: 354.2206.

Example 2v (7R, 9aS) -7- ( 3- methoxy - phenoxy) methyl: mp113~115 ℃; HRMS calcd for _{C 20 H 26 N 4 O 2} : 354.2
056; found: 354.2041.

Example 2w (7R, 9aS) -7- (3-acetamido-phenoxy) methyl: mp 156-158 ° C; HRMS calculated for C ₂₁ H ₂₇ N ₅ O ₂ : 38
1.2165; found: 381.2160.

Example 2x (7R, 9aS) -7- (2-cyano-phenoxydimethyl: m
_{p250~252 ℃; C 20 H 23 N} 5 HRMS calcd for O: 349.1903;
Found: 349.1932.

Example 2y (7R, 9aS) -7- (3-cyano-phenoxy) methyl: m
_{p241,5~243 ℃; C 20 H 23 N} 5 HRMS calcd for O: 349.190
3; Found: 349.1897.

Example 2z (7R, 9aS) -7- (3-dimethylamino-phenoxy)
Methyl: mp 80-82 ° C; HRMS calculated for C ₂₁ H ₂₉ N ₅ O: 367.
2372; found: 367.2357.

Example 2aa (7R, 9aS) -7- ( 3,4- difluoro - phenoxy) _{methyl: mp252~254 ℃; C 19 H 22} F 2 N 4 HRMS calcd for O: 36
0.1762; found: 360.1763.

Example 2ab (7S, 9aR) -7- ( 4- fluoro - phenoxy) _{methyl: mp281~282 ℃; C 19 H 23} FN 4 HRMS calcd for O: 342.1
856; Found: 342.1841.

Example 3 (7R, 9aS) -7- (Substituted) methyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazines The compound having the above formula was prepared according to Example 1 (7R, 9a
S) -7-Hydroxymethyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine It was manufactured using (Production Example 5) and an appropriate phenol. Purification is generally
Flash silica gel chromatography was achieved using a mixture of ethyl acetate and hexane or a mixture of chloroform and methanol as the eluting solvent. The stereochemical configuration, melting point of 7-substituent, monohydrochloride and HRMS or ¹³ C NMR data are shown.

Example 3a (7R, 9aS) -7- (3-cyanophenoxy) methyl; mp1
Ninety-two to one hundred ninety-four ° C.; HRMS for C ₂₀ H ₂₂ FN ₅ O: Calculated: 367.1808;
Found: 367.1821.

Example 3b (7R, 9aS) -7- (4-cyanophenoxy) methyl; mp2
_{56~257 ℃; C 20 H 22 FN} 5 HRMS calcd for O: 367.1808; Found: 367.1793.

Example 3c (7R, 9aS) -7- {2-methoxy-3- (1-methyl)
Ethyl - phenoxy) _{methyl; mp> 286 ℃; C 23} H 32 HRMS calcd for FN ₄ O _2: 414.2424; Found: 414.2418.

Example 3d (7R, 9aS) -7- (2-fluorophenoxy) methyl; m
_{p209~210 ℃; C 29 H 22 F} 2 N 4 HRMS for O: Calculated: 360.176
2; measured: 360.1767.

Example 3e (7R, 9aS) -7- (3-fluorophenoxy) methyl; m
_{p229~232 ℃; C 19 H 22 F} 2 N 4 HRMS for O: Calculated: 360.176
7; Found: 360.1755.

Example 3f (7R, 9aS) -7- (4-fluorophenoxy) methyl; m
_{p249~254 ℃; C 19 H 22 F} 2 N 4 HRMS for O: Calculated: 360.176
7; Found: 360.1741.

Example 3g (7R, 9aS) -7- (3,4-difluorophenoxy) methyl; mp 229 ° -236 ° C .; HRMS for C ₁₉ H ₂₁ F ₃ N ₄ O: Calculated: 37
8.1667; found: 378.1660.

Example 3h (7R, 9aS) -7- ( 3,5- difluorophenoxy) _{methyl; mp248~250 ℃; C 19 H 21} F 3 N 4 HRMS calcd for O: 378.
1667; found: 378.1680.

Example 3i (7R, 9aS) -7- (4-iodophenoxy) methyl; mp2
84-286 ° C; HRMS calculated for C ₁₉ H ₂₂ FIN ₄ O: 468.0822;
Found: 468.0785.

Example 4 (7RS, 9aSR) -7-phenoxymethyl-2- (5-fluoro-4-thiomethylpyrimidin-2-yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine The title compound was phenol and (7R
S, 9aSR) -7-Hydroxymethyl-2- (5-fluoro-4-thiomethyl) pyrimidin-2-yl) -2,3,4,6,
It was prepared using 7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (Preparation Example 6). mp (HCl) 192
~ 198 ° C. Anal calculated values for C ₂₀ H ₂₅ FN ₄ OS: C, 61.82; H,
6.49; N, 14.42; Found: C, 61.52; H, 6.56; N, 14.42.

Example 5 (7RS, 9aSR) -7-phenoxymethyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1 , 2-a] Pyrazine 3.74 g (9.63 mmol) of (7RS, 9aSR) -7-phenoxymethyl-2- (5-fluoro-4-thiomethylpyrimidin-2-yl) -2,3,4,6,7,8,9, 9a-octahydro-1H
A 200 mL ethanol solution of -pyrido [1,2-a] pyrazine (Example 4) was treated with 0.3 g of Raney nickel and the mixture was refluxed for 2 hours. An additional 0.3 g of catalyst was added and reflux continued for 24 hours. A third amount of catalyst (0.3 g) was added and refluxed for 4 hours. A fourth amount of catalyst (0.3 g) was added and refluxed for a further 4 hours. The mixture was cooled to room temperature and celite
Passed through e), washed with ethanol and evaporated. Purification by flash silica gel chromatography, eluting with methylene chloride and 99: 1 methylene chloride: methanol, gave 1.30 g (39%) of the title compound. mp (.HCl) 215-217 ° C. HRMS for C ₁₉ H ₂₃ FN ₄ O
Calculated: 342.1185; Measured: 342.1585.

Example 6 (7RS, 9aSR) -7- (4-Fluorophenoxy) methyl-2- (5-fluoro-4-thiomethyl-pyrimidine-
2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine The title compound was prepared according to Example 1 using 4-fluorophenol and (7RS, 9aSR) -7-hydroxymethyl-2-.
(5-Fluoro-4-thiomethylpyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (Production Example 6) And manufactured using. mp (.HCl) 201-210 ° C .: ¹³ C NMR (base, CDCl ₃ ):
δ11.5,27.0,29.0,36.4,44.3,49.8,54.8,58.8,60.7,71.
6,115.35,115.45,115.59,115.90,140.4,140.7,150.9,15
5.1,158.8. HRSM calcd for _{C 20 H 24 F 2 N 4} OS: 406.166;
Found: 406.161.

Example 7 (7RS, 9aSR) -7- (4-fluorophenyl) methyl-
2- (5-fluoropyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine Using the procedure described in Example 5, 8.23 g (20.3 mmo
l) (7RS, 9aSR) -7- (4-fluorophenoxy)
Methyl-2- (5-fluoro-4-thiomethylpyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H
-Pyrido [1,2-a] pyrazine gave 3.4 g of the title compound. mp (.HCl) 249-253 ° C. C ₁₉ H ₂₂ F ₂ N Calcd for _{4 O · HCl: C, 57.50} ; H, 5.84; N, 14.12; measurements: C, 5
7.40; H, 5.84; N, 13.99.

Example 8 (7SR, 9aSR) -7-{(4-Fluorophenoxy) methyl} -2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,9
9a-octahydro-1H-pyrido [1,2-a] pyrazine 0.600 g (2.43 mmol) of (7SR, 9aSR) -7-hydroxymethyl-2- (pyrimidin-2-yl) -2,3,4,6,7,8,
A solution of 9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (U.S. Pat. No. 5,122,525) and 0.34 mL (2.7 mmol) of triethylamine in 0.20 mL of a 0.degree.
(5 mmol) of methanesulfonyl chloride. Ten
After minutes, the mixture was diluted with water, basified with 1 M NaOH, separated, and the mixture was extracted with more methylene chloride (2x). The combined organic layers were washed with water (1x), dried (magnesium sulfate), filtered and evaporated to 0.77g
(2.6 mmol) of the mesylate.

0.82 g (7.3 mmol) of 4-fluorophenol in 8 ml of DMF
The solution was treated with 0.35 g (8.8 mmol) of sodium hydride (60
% Oil dispersion) and reacted at 40-50 ° C for 2 hours. The reaction mixture was cooled to room temperature and 0.77 g (2.6 mmol) of the above mesylate in 8 mL DMF was added. The reaction was then heated to 100 ° C. for 16 hours. After cooling to room temperature, the solvent was evaporated, the residue was taken up in water, adjusted to pH 2 with 1 M HCl and washed with ethyl acetate. The aqueous phase was made basic (pH 11) with 1 M NaOH and extracted with ethyl acetate (3x). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to give 0.430 g of crude product. Purification by flash chromatography on silica gel, eluting with 90:10 ethyl acetate: hexane, gave 0.340 g (38%) of the title compound. 0.29 g of free base ethanol
The salt was prepared by mixing the ethyl acetate solution with 98 mg of maleic acid in ethanol and evaporating to dryness. The white solid is triturated in ether and dried under reduced pressure to give 0.35 g
Of salt. _{mp (· C 4 H 4 O} 4) 128~139 ℃. ¹³ C NMR (base, CDCl ₃ ): δ 24.8, 25.2, 33.8, 43.6, 49.1, 54.9, 56.
6,61.1,69.5,109.7,115.48,115.25,115.58,115.83,155.
4,157.7,161.5. Calculated value for C ₁₉ H ₂₃ N ₄ OF: C, 66.6
4; H, 6.77; N, 16.36; Found: C, 66.28; H, 7.02; N, 16.45.

Example 9 (7RS, 9aSR) -7-phenoxymethyl-2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H
-Pyrido [1,2-a] pyrazine 1.0 g (4.0 mmol) of (7RS, 9aSR) -7-hydroxymethyl-2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,
A solution of 9a-octahydro-1H-pyrido [1,2-a] pyrazine (Preparation Example 3) in 20 mL of dry methylene chloride was cooled to 0 ° C., and 0.57 mL (4.4 mol) of triethylamine and 0.33 mL
(4.2 mmol) of methanesulfonyl chloride was treated dropwise. After 15 minutes, water was added and the pH was adjusted to 11 with 1N NaOH. The layers were separated and the aqueous phase was extracted with methylene chloride (2x). Dry the combined organic phases (over magnesium sulfate)
And evaporated to give 1.0 g (76%) of mesylate.

A mixture of 10 mL DMF, 0.90 g (9.6 mmol) phenol and 0.45 g (10.2 mmol) NaH (60% oil dispersion) in a drying flask was stirred at 40-50 ° C. for 1.5 hours. After cooling to room temperature, the mesylate was added to 10 mL of DMF and the solution was heated to 100-110 ° C. for 16 hours. After cooling to room temperature, water was added, the pH was adjusted to 11 with 1N NaOH, the mixture was extracted with ethyl acetate (3x), dried (magnesium sulfate), filtered and evaporated. Triturate the crude product with a few mL of water,
Redissolved in ethyl acetate, dried (magnesium sulfate), filtered and evaporated. Flash chromatography on silica gel with ethyl acetate gave a white solid,
0.68 g of free base was provided. mp (.2HCl) 218-223 ° C.
¹³ C NMR (base, CDCl ₃ ): δ 27.0, 29.0, 36.4, 43.6, 49.
1,54.9,58.8,60.8,70.9,109.8,114.5,120.6,129.4,157.
7,159.0,161.5. Calcd for _{C 19 H 24 NO 4 · 2HCl} : C, 57.
43; H, 6.60, N, 14.10; Found: C, 57.54; H, 6.88, N, 13.83.

Example 10 7- (Substituted phenoxymethyl) -2- (pyrimidine-2
-Yl) -2,3,4,6,7,8,9,9a-Octahydro-1H-pyrido [1,2-a] pyrazines The compound represented by the above formula was prepared according to Example 8 (7SR,
9aSR) -7-Hydroxymethyl-2- (pyrimidine-2
-Yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (US Pat. No. 5,122,525) and a suitable phenol. Purification was generally achieved by flash silica gel chromatography using a mixture of ethyl acetate and hexane or a mixture of chloroform and methanol as the eluting solvent. Stereochemical configuration, 7-phenoxymethyl substituent, melting point and HRMS of monohydrochloride or combustion analysis or
^13C NMR data is shown.

Example 10a (7SR, 9aSR) -7- ( 4- acetamidophenoxy) methyl; mp123 ℃ (decomposition); ¹³ CNMR (base, CDCl _3): δ2
4.3,24.8,25.1,33.7,43.6,49.1,54.8,56.6,61.1,69.1,1
09.7,114.9,121.9,130.9,156.2,157.7,161.5,168.3.

Example 10b (7SR, 9aSR) -7 - {(4- trifluoromethyl) phenoxy} _{methyl; mp104~119 ℃; C 20 H 23} F 3 N 4 O for HRM
S Calculated: 392.1819; Found: 392.1833.

Example 10c (7SR, 9aSR) -7 - {(4- methoxy) phenoxy} _{methyl; mp112~114 ℃; C 20 H 26} N 4 O Calcd for _{2 · HCl: C, 61.44;} H6.96; N , 14.33; Found: C, 61.23; H, 7.29; N1
4.51.

Example 10d (7SR, 9aSR) -7 - {(4- carboethoxy) phenoxy} methyl; mp189~191 ℃; HRMS Calcd for _{C 22 H 28 N 4 O 3} : 396.2162; Found: 396.2179.

Example 11 (7R, 9aS) -7- (4-fluorophenoxymethyl)-
2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine The title compound was prepared according to Preparation Example 3 using 2-chloropyrimidine and (7R, 9aS) -7- (4-fluorophenoxymethyl) -2,3,4,6,7,8,9,9a-octahydro-1H. -Pyrido [1,2-a] pyrazine (Preparation Example 8). mp
(.HCl) 283-285 ° C. HRMS Calcd for C ₁₉ H ₂₃ FN ₄ O:
342.1856; found: 342.1867.

Example 12 (7R, 9aS) -7- (2-phenyl) ethyl-2- (5-
Fluoropyrimidin-2-yl) -2,3,4,6,7,8,9,9a-
Octahydro-1H-pyrido [1,2-a] pyrazine 3.75 g (14.1 mmol) of (7R, 9aS) -7-hydroxymethyl-2- (5-fluoropyrimidin-2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine (Preparation Example 5), 2.48 g (21.2 mmol) of N-
A mixture of methylmorpholine-N-oxide, 5.0 g of 4 molecular sieves, 0.495 g (1.41 mmol) of tetrapropylammonium perthenate and 375 mL of methylene chloride was stirred at ambient temperature for 2 hours. Quench the reaction with saturated sodium thiosulfate and add Celite
e) through. The liquor was washed with brine, dried (magnesium sulfate), filtered and evaporated. 95: 5
Purification by flash silica gel chromatography with chloroform: methanol yielded 2.27 g (61%) of (7R, 9aS) -7-formyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,6. , 7,8,9,9a-octahydro-
1H-pyrido [1,2-a] pyrazine was provided.

A solution of 1.70 g (4.38 mmol) of benzyltriphenylphosphonium chloride in 20 mL of dry THF was cooled to −78 ° C.
It was treated with 1.75 mL (4.38 mmol) of n-butyllithium (2.5 M hexane solution). After 15 minutes, 1.05 g (3.
98 mmol) of (7R, 9aS) -7-formyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1, 2-a] Pyrazine was added dropwise over 30 minutes, the cooling bath was removed and the solution was slowly warmed to ambient temperature overnight (16 hours). The solution was concentrated under reduced pressure and the residue was partitioned between ethyl ether and water. The organic layer was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography in a petroleum ether: ethyl ether ratio of 4: 1 to 3: 1 gives the following isomer 7- (2-phenyl) ethenyl-2-.
(5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,
9,9a-Octahydro-1H-pyrido [1,2-a] pyrazine:
E- (7R, 9aS), 0.19 g (Rf = 3: 1 hexane: ethyl acetate)
0.75): Z- (7R, 9aS), 0.16 g (Rf = 0.47 in 3: 1 hexane: ethyl acetate); E- (7R, 9aS), 0.46 g (3: 1 hexane:
Rf = 0.23 with ethyl acetate).

0.15 g (0.44 mmol) of Z- (7R, 9aS) -7- (2-phenyl) ethenyl-2- (5-fluoropyrimidine-2
-Yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine, 0.015 g of 10% palladium on activated carbon and 25 mL of ethanol in a Parr apparatus. Under 40 psig of hydrogen gas for 6 hours. The mixture was passed through celite and the liquid was concentrated to give 0.124 g (83%) of (7R, 9
aS) -7- (2-Phenyl) ethyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2 -A] provided pyrazine. mp
(.HCl) 250-252 ° C. C ₂₀ H ₂₆ FN ₄ HRM for O (MH +)
S Calculated: 341.2142; Found: 341.2126.

Example 13 (7SR, 9aSR) -7-phenoxymethyl-2- (pyridin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-
Pyrido [1,2-a] pyrazine The title compound was phenol and (7S
R, 9aSR) -Hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-2-pyridin-2-yl-1H-pyrido [1,2
-A] pyrazine (US Patent 5,122,525). ¹³ C NMR (base, CDCl ₃ ): δ 24.8, 25.3, 33.8, 45.
1,50.7,54.8,56.6,61.0,68.8,107.1,113.1,114.7,120.
5,129.4,137.4,148.0,159.3,159.4. For C ₂₀ H ₂₅ N ₃ O
HRMS calc: 323.2000; found: 323.2003.

Example 14 (7RS, 9aSR) -7-phenoxymethyl-2- (pyridin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-
Pyrido [1,2-a] pyrazine The title compound was prepared according to Example 9 using (7RS, 9aSR) -hydroxymethyl-2- (pyridin-2-yl) -2,3,4,6,
It was prepared from 7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (Preparation Example 11) and phenol. mp
(.HCl) 238-241 ° C. ¹³ C NMR (base, CDCl ₃ ): δ 27.
0,29.2,36.4,45.2,50.8,54.8,58.8,60.7,70.9,107.0,11
3.2,114.5,120.7,113.2,114.5,120.7,129.4,137.5,148.
0,159.0,159.4. Calculated value for C ₂₀ H ₂₅ N ₃ O: C, 74.2
6; H, 7.79; N 12.99; Found: C, 74.12; H, 7.84; N, 12.86.

Example 15 (7RS, 9aSR) -7- (4-Fluorophenoxy) methyl-2- (3,5-dichloropyridin-2-yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine 0.75 g (4.4 mmol) of (7RS, 9aSR) -7-hydroxymethyl-2-, 3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine, 4.02 A mixture of g (22.1 mmol) of 2,3,5-trichloropyridine, 1.12 g (10.6 mmol) of sodium carbonate and 30 mL of isoamyl alcohol was refluxed for 72 hours. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium carbonate. The organic layer was dried (magnesium sulfate), filtered, evaporated and the crude product was purified by flash chromatography on silica gel, eluting with 95: 5 chloroform: methanol to give 1.10 g (80%) of (7
RS, 9aSR) -7-Hydroxymethyl-2- (3,5-dichloropyridin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2 -A] provided pyrazine.

0.50 g (1.58 mmol) of (7RS, 9aSR) -7-hydroxymethyl-2- (3,5-dichloropyridin-2-yl)-
2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] 0.266 g (2.32 mmol) of pyrazine in 40 mL THF solution
-Fluorophenol, 0.498 g (1.90 mmol) of triphenylphosphine and 0.30 mL (1.90 mmol) of diethyl azodicarboxylate were stirred at room temperature for 16 hours. The mixture is diluted with ethyl acetate and the excess HCl (g) in ether
Processed. The solvent was evaporated and the residue was 1: 1 ethyl acetate:
Washed repeatedly with ether. The white powder was dissolved in chloroform, washed with 1 M NaOH (2x), dried (magnesium sulfate), filtered and evaporated. The crude product is
50:50 by flash silica gel chromatography
Purification by elution with ethyl acetate: hexane gave 0.566 g (87
%) Of the title compound. mp (.HCl) 247-248 ° C.
¹³ C NMR (base, CDCl ₃ ): δ 27.1, 29.0, 36.4, 49.0, 54.
4,54.8,58.6,60.7,71.7,115.36,115.47,115.59,115.89,
122.3, 124.0, 138.2, 155.1, 155.6, 156.6, 158.8. C ₂₀ H ₂₂ C
HRMS Calcd for l ₂ FN ₃ O: 409.1124; Found: 409.114
1.

Example 16 7- (4-Fluorophenoxy) methyl-2- (substituted-
Pyridin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazines These compounds were prepared according to Example 15 using (7RS, 9aSR) -7
-Hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (U.S. Pat.
From 4), in the first step, the appropriate 2-chloro or 2-bromopyridine was produced in the second step, using 4-fluorophenol. Purification was generally achieved by flash silica gel chromatography using a mixture of ethyl acetate and hexane or a mixture of chloroform and methanol as the eluting solvent. The stereochemistry, substituted pyridin-2-yl substituents, melting point of monohydrochloride and HRMS data are shown.

Example 16a (7RS, 9aSR), 2- (3-cyanopyridin-2-yl): m
p194-195 ° C; HRMS calculated for C ₂₁ H ₂₃ FN ₄ O: 366.1855;
Found: 366.1845.

Example 16b (7RS, 9aSR), 2- (4-methylpyridin-2-yl): m
p264-266 ° C; HRMS calculated for C ₂₁ H ₂₆ FN ₃ O: 355.2060;
Found: 355.2075.

Example 16c (7RS, 9aSR), 2- (5-bromopyridin-2-yl): m
_{p214~215 ℃; C 20 H 23 BrFN} 3 HRMS calcd for O: 419.100
8; Found: 419.1037.

Example 16d (7RS, 9aSR), 2- (3-chloropyridin-2-yl): m
_{p174~175 ℃; C 20 H 23 ClFN} 3 HRMS calcd for O: 375.151
4; Found: 375.1528.

Example 17 (7RS, 9aSR) -7-phenoxymethyl-2- (5-chloropyridin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1 , 2-a] Pyrazine The title compound was 2,5-dichloropyridine, (7RS, 9aSR) -7-hydroxymethyl-2,3,4,6, according to Example 15.
Prepared using 7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (U.S. Pat. No. 5,326,874) and phenol. mp (.HCl) 218-224 ° C. ¹³ CNMR (base,
CDCl ₃ ): δ27.0, 29.1, 36.4, 45.3, 50.9, 54.6, 58.8, 60.
5,70.9,107.8,114.5,120.1,120.7,129.4,137.1,146.2,1
57.6,159.0. Calculated value for C ₂₀ H ₂₄ ClN ₃ O: C, 67.12;
H, 6.76: N, 11.74; Found: C 67.22; H 6.85; N, 11.49.

Example 18 (7R, 9aS) -7- (4-Fluorophenoxy) methyl-
2- (pyridin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine The title compound was prepared according to Preparation Example 11 using 2-bromopyridine and (7R, 9aS) -7- (4-fluorophenoxy) methyl-2,3,4,6,7,8,9,9a-octahydro-1H-. It was synthesized using pyrido [1,2-a] pyrazine (Production Example 8). mp (.HCl) 261-263 ° C. HRMS for C ₂₀ H ₂₄ FN ₃ O
Calculated: 341.1903; Found: 341.1929.

Example 19 (7R, 9aS) -7- (4-Fluorophenoxy) methyl-
2- (5-chloropyridin-2-yl) -2,3,4,6,7,8,
9,9a-octahydro-1H-pyrido [1,2-a] pyrazine The title compound was prepared according to Preparation Example 11 using 2,5-dichloropyridine and (7R, 9aS) -7- (4-fluorophenoxy) methyl-2,3,4,6,7,8,9,9a-octahydro- Produced using 1H-pyrido [1,2-a] pyrazine (Production Example 8). mp (.HCl) 237-238 ° C. ¹³ CNMR (base, CDC
l ₃ ): δ27.0, 29.1, 36.4, 45.3, 50.9, 54.6, 58.7, 60.5, 7
1.6,107.7,115.36,115.47,115.60,115.90,120.1,137.1,
146.3, 155.1, 155.6, 157.6, 158.8. HRMS Calcd for _{C 20 H 23 ClFN 3 O:} 375.1514; Found: 375.1544.

Example 20 (7R, 9aS) -7- (4-Fluorophenoxy) methyl-
2- (6-chloropyridazin-3-yl) -2,3,4,6,7,
8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine The title compound was 3,6-dichloropyridazine and (7R, 9aS) -7- (4-fluorophenoxy) methyl-2,3,4,6,7,8,9,9a-octahydro- according to Preparation Example 3. Prepared with 1H-pyrido [1,2-a] pyrazine. mp (HCl) 265
~ 270 ° C. ¹³ C NMR (base, CDCl ₃ ): δ 26.8, 29.0, 36.4,
45.1,50.4,54.4,58.6,60.3,71.5,115.2,115.3,115.4,11
5.6,115.9,128.7,146.7,155.0,155.6,158.76,158.82. C
₁₉ H ₂₂ ClFN ₄ HRMS calcd for O: 376.1461; Found: 376.
1453.

Example 21 (7S, 9aR) -7- (4-Fluorophenoxy) methyl-
2- (5-fluoropyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine The title compound was prepared according to Production Example 3 using 2-chloro-5-fluoropyrimidine and (7S, 9aR) -7- (4-fluorophenoxy) methyl-2,3,4,6,7,8,9,9a- Manufactured with octahydro-1H-pyrido [1,2-a] pyrazine (Production Example 9). mp (.HCl) 251-252 ° C. ¹³ CNMR (base, CDCl
₃ ): δ27.0, 29.0, 36.4, 44.3, 49.8, 54.8, 58.8, 60.7, 71.
6,115.35,115.45,115.59,115.89,145.0,145.3,149.9,15
3.2, 155.1, 155.6, 158.7, 158.8. HR for C ₁₉ H ₂₂ F ₂ N ₄ O
MS calc: 360.1762; found: 360.1763.

Example 22 (7R, 9aR) -7- (4-Fluorophenoxy) methyl-
2- (5-fluoropyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine The title compound was prepared according to Preparation Example 3 using 2-chloro-5-fluoropyrimidine and (7R, 9R) -7- (4-fluorophenoxy) methyl-2,3,4,6,7,8,9,9a- Prepared with octahydro-1H-pyrido [1,2-a] pyrazine (Preparation Example 10). mp (.HCl) 232.5-324 ° C. ¹³ CNMR (base, CD
Cl ₃ ): δ24.8,25.1,33.8,44.3,49.7,54.8,56.6,61.0,6
9.5,115.48,115.53,115.59,115.83,145.0,145.3,149.9,
153.1,155.4,155.5,158.69,158.74. _{C 19 H 22 F 2 N 4} HRMS calcd for O: 360.1762; Found: 360.1755.

Example 23 (7RS, 9aSR) -7- (4-Fluorophenoxy) methyl-2- (2-cyano-4-fluorophenyl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine 1.05 g (6.17 mmol) of (7RS, 9aSR) -7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (US Pat. 5,326,874) and 1.29
20 mL of g (9.25 mmol) of 2,5-difluorobenzonitrile
The DMSO mixture was heated to 100 ° C. for 16 hours. The mixture was cooled to room temperature, acidified with 1M HCl, washed with ether (3x), basified with concentrated ammonium hydroxide and extracted with ethyl acetate (3x). The combined organic layers were washed with water (3x), dried (magnesium sulfate), filtered and evaporated. Silica gel M in 90:10 chloroform: methanol
Purification by PLC yielded 0.51 g of (7RS, 9aSR) -7-hydroxymethyl-2- (2-cyano-4-fluorophenyl)
-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2
-A] provided pyrazine.

0.51 g (1.8 mmol) of (7RS, 9aSR) -7-hydroxymethyl-2- (2-cyano-4-fluorophenyl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] A solution of pyrazine, 0.555 g (2.12 mmol) of triphenylphosphine and 0.296 g (2.64 mmol) of 4-fluorophenol in 8 mL of dry THF was treated with 0.368 g (2.12 mmol) of diethyl azodicarboxylate at ambient temperature For 24 hours. The mixture was diluted with ether and 1M HCl was added until a gummy residue formed. The layers were separated and the aqueous layer was washed with ether (3x). The aqueous layer was combined with the gummy residue, dissolved in a mixture of ethyl acetate and 10% ammonium hydroxide, the layers separated, and the aqueous layer further extracted with ethyl acetate (2.
x). The organic layer was evaporated, the residue was dissolved in chloroform, washed with 1M NaOH (3x), dried (magnesium sulfate), filtered and evaporated. The product was dissolved in absolute ethanol, filtered and evaporated to give 0.21 g of the title compound. mp (.HCl) 235-240 ° C. C ₂₂ H ₂₃ F ₂ N
HRMS calc for ₃ O: 383.1809; found; 383.1796.

Example 24 (7R, 9aS) -7- (4-Fluorophenoxy) methyl-
2- (2-amino-4-fluorophenyl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine 4.38 g (25.8 mmol) of (7R, 9aS) -7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (Production Example 1), 4.19mL (38.7mmo
l) 2,5-difluoronitrobenzene and 5.46 g (51.
A solution of 5 mmol) sodium carbonate in 25 mL DMSO was heated to 95 ° C. for 16 hours. The mixture was cooled to room temperature, acidified with 1M HCl and washed with ethyl ether (3x). The aqueous layer was made basic with concentrated ammonium hydroxide and extracted with ethyl acetate (3x). The combined organic layers were washed with water (3x), dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 90:10 chloroform: methanol afforded 6.19 g (78%) of (7R, 9a
S) -7-Hydroxymethyl-2- (4-fluoro-2
-Nitrophenyl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine.

3.0 g (9.7 mmol) of (7R, 9aS) -7-hydroxymethyl-2- (4-fluoro-2-nitrophenyl) -2,3,
4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a]
0.30 gn of a solution of pyrazine in 50 mL methanol and 50 mL THF
o Treated with 10% Pd / C and 1.5 psi with 30 psi hydrogen
Time processed. The catalyst was removed by filtration and the red solution was concentrated, yielding 2.65 g (98%) of (7R, 9aS) -7-hydroxymethyl-2- (2-amino-4-fluorophenyl)-
2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] Pyrazine was given.

4.12 g (14.8 mmol) of (7R, 9aS) -7-hydroxymethyl-2- (2-amino-4-fluorophenyl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] A solution of pyrazine, 2.48 g (22.2 mmol) of 4-fluorophenol and 4.65 g (17.7 mmol) of triphenylphosphine in 225 mL of THF was treated with 2.79 mL (17.7 mmol) of diethylazodicarboxylate and treated at room temperature for 4 hours. Stirred for days. Evaporate the solvent, dissolve the residue in 1: 1 ethyl acetate: ethyl ether and concentrate the residue in ether until precipitation stops.
Treated with HCl (g). The mixture was filtered and the solid was washed repeatedly with ethyl acetate. Chloroform and 1M solid
Was dissolved in a mixture of sodium hydroxide, the layers were separated, the organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash chromatography with 60:40 ethyl acetate: hexane gave 1.69 g of the title compound. mp (.HCl) 144-149 ° C. For C ₂₁ H ₂₅ F ₂ N ₃ O
HRMS calc: 373.1966; found: 373.1958.

Example 25 (7RS, 9aSR) -7- (4-Fluorophenoxy) methyl-2- (4-fluorophenyl) -2,3,4,6,7,8,9,9a-
Octahydro-1H-pyrido [1,2-a] pyrazine 1.53 g (4.10 mmol) of (7R, 9aS) -7-hydroxymethyl-2- (2-amino-4-fluorophenyl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] 1.21 mL of a 160 mL THF solution of pyrazine (Example 24)
(9.02 mmol) 97% isoamyl nitrite 100 mL THF
The solution was added over 2 hours. After the addition was complete, the solution was heated at reflux for 4 days. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with 1M sodium hydroxide (3x). The organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 50:50 ethyl acetate: hexane gave 0.75 g (52
%) Of a yellow solid. mp (.HCl) 221-223 ° C. C ₂₁
H ₂₄ F ₂ N ₂ HRMS calcd for O: 358.1857; Found: 358.187
Five.

Example 26 (7R, 9aS) -7-phenoxymethyl-2-phenyl-2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine 0.500 g (1.89 mmol) of (7R, 9aS) -7- (4-fluorophenoxy) methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a ] Pyrazine (Production Example 8), 0.4
00 g (2.84 mmol) of 4-fluoronitrobenzene and
A mixture of 0.401 g (3.78 mmol) of sodium carbonate in 15 mL DMSO was heated to 95 ° C. for 16 hours. Cool the mixture to room temperature,
Acidify with 1M HCl, wash with ethyl ether (3x),
Make basic with concentrated ammonium hydroxide and ethyl acetate (3x)
Extracted. The combined organic layers were washed with water and brine, dried (magnesium sulfate), filtered and evaporated to give 0.614 g of (7R, 9aS) -7- (4-fluorophenoxy) methyl-2- (4 -Nitrophenyl) -2,3,4,6,
7,8,9,9a-Octahydro-1H-pyrido [1,2-a] pyrazine was provided.

0.600 g (1.56 mmol) of (7R, 9aS) -7- (4-fluorophenoxy) methyl-2- (4-nitrophenyl)-
2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] A mixture of pyrazine and 90 mg of 10% Pd / C in 25 mL THF was placed in a Parr hydrogenator at 30 psi for 4 hours. The catalyst was removed by filtration through celite and the liquid was evaporated to 0.45
g (82%) of (7R, 9aS) -7- (4-fluorophenoxy) methyl-2 (4-aminophenyl) -2,3,4,6,7,8,
9,9a-Octahydro-1H-pyrido [1,2-a] pyrazine was provided.

0.400 g (1.13 mmol) of (7R, 9aS) -7- (4-fluorophenoxy) methyl-2 (4-aminophenyl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] A solution of pyrazine in 20 mL of THF was added dropwise to a solution of 0.33 mL (2.48 mmol) of isoamyl nitrite in 15 mL of THF. After the addition was complete, the solution was refluxed for 24 hours. Evaporate the solvent, dissolve the residue in ethyl acetate, wash with 1M sodium hydroxide (3x) and brine (1x), (with magnesium sulfate)
Dry, pass and evaporate. Purification by flash silica gel chromatography in ethyl acetate yields 0.060 g
This gave (16%) of the title compound. mp (HCl) 247-252
° C. HRMS Calcd for _{C 21 H 25 FN 2 O:} 340.1951; Found: 3
40.1989.

Example 27 (7RS, 9aSR) -7- (4-Fluorophenoxy) methyl-2- (6-methoxypyridin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine Following the procedure reported by Wynberg (J. Org. Chem. 1993, 58, 5101), 0.50 g (2.9 mmol) of racemic (7R
(S, 9aSR) -7-hydroxymethyl-2,3,4,6,7,8,9,9a-
10 mL of octahydro-1H-pyrido [1,2-a] pyrazine
The dry THF 0 ° C solution was treated with 2.59 mL (6.5 mmol) of n-butyllithium (2.5 M hexane solution). Bring the mixture to 0 ° C for 30
For 1 minute at room temperature, and 0.39 mL (2.94 mmol) of 2,6-
Dimethoxypyridine was added and the solution was refluxed for 16 hours. After cooling to room temperature, the mixture was poured into 1M HCl and toluene (3
Washed in x). The aqueous layer was made basic with 1M NaOH and extracted with toluene (1 ×) and ethyl acetate (1 ×). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to give a yellow oil. Purification by flash silica gel chromatography with 9: 1 chloroform; methanol yielded 0.304 g (37%) of (7RS, 9aSR)-
7-hydroxymethyl-2- (6-methoxypyridine-
2-yl) -2,3,4,6,7,8,9,9a-Octahydro-1H-pyrido [1,2-a] pyrazine.

0.30 g (1.1 mmol) of (7RS, 9aSR) -7-hydroxymethyl-2- (6-methoxypyridin-2-yl) -2,3,
4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a]
A 20 mL THF solution of pyrazine, 0.182 g (1.62 mmol) of 4-fluorophenol and 0.340 g (1.30 mmol) of triphenylphosphine, and 0.205 g (1.30 mmol) of diethylazodicarboxylate was stirred at room temperature for 16 hours. .
The solvent was evaporated, the residue was dissolved in ether and 1M HCl (2
x). The combined aqueous layers were made basic with concentrated ammonium hydroxide and extracted with ethyl acetate (3x). The combined organic layers were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 50:50 ethyl acetate: hexane gave 0.300 g
(75%) yielded yellow crystals. mp (HCl) 228-230
° C. HRMS Calcd for _{C 21 H 26 FN 3 O 2} : 371.2009; Found:
371.2001.

Example 28 (7RS, 9aSR) -7- (4-Fluorophenoxy) methyl-2,3,4,6,7,8,9,9a-octahydro-2- (5-fluoropyridin-2-yl)- 1H-pyrido [1,2-a] pyrazine According to Schwartz (J. Am. Chem. Soc. 1986, 108, 2445),
0.300 g (0.714 mmol) of (7RS, 9aSR) -7- (4-fluorophenoxy) methyl- (5-bromopyridine-2-
Yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (Example 16) in 6.5 mL THF: hexane: ethyl ether (4: 1) 1) The solution was cooled to -100 ° C under nitrogen. n-Butyllithium (0.57 mL, 2.5 M hexane solution) was added dropwise, and the mixture was stirred for 15 minutes. A solution of N-fluorodibenzenesulfonamide (0.34 g, 1.07 mmol) in ethyl ether was added and the solution was stirred for 20 minutes and then allowed to warm to room temperature over 20 hours. Water was added and the mixture was extracted with ethyl acetate (3x), dried (magnesium sulfate),
And evaporated. Purification by flash silica gel chromatography with 50:50 ethyl acetate: hexane provided 0.038 g (15%) of the title compound. mp (・ HC
l) 214-215 ° C. HRMS Calcd for _{C 20 H 23 F 2 N 3} O: 359.1
809; found: 359.1795.

Example 29 (7RS, 9aSR) -7-phenoxymethyl-2- (2-chloropyrimidin-4-yl) 2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1, 2-a] pyrazine (7RS, 9aSR) -7-hydroxymethyl-2,3,4,6,7,8,
A mixture of 9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (US Pat. No. 5,326,874) and 2,4-dichloropyrimidine was combined according to Preparation Example 3. The product from this reaction was coupled with phenol according to Example 1 to give the title compound. mp (.HCl) 227-233 ° C (decomposition). C ₁₉
H ₂₃ ClN ₄ HRMS calcd for O: 358.1560; Found: 358.156
0.

Example 30 (7RS, 9aSR) -7-phenoxymethyl-2- (pyrazin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-
Pyrido [1,2-a] pyrazine (7RS, 9aSR) -7-hydroxymethyl-2,3,4,6,7,8,
A mixture of 9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (US Pat. No. 5,326,874) and 2-chloropyrazine was combined according to Preparation Example 3. The product from this reaction was coupled with phenol according to Example 1 to give the title compound. mp (.HCl) 217-219 ° C. HRMS Calcd for _{C 19 H 24 N 4 O:} 324.1945; Found: 324.1981.

Example 31 (7RS, 9aSR) -7-phenoxymethyl-2- (6-chloropyrazin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1 , 2-a] Pyrazine (7RS, 9aSR) -7-hydroxymethyl-2,3,4,6,7,8,
A mixture of 9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (US Pat. No. 5,326,874) and 2,6-dichloropyrazine was combined according to Preparation Example 3. The product from this reaction was coupled with phenol according to Example 1 to give the title compound. mp (.HCl) 247 ° C (decomposition). C ₁₉ H ₂₃ ClN ₄
HRMS calc for O: 358.1560; found: 358.160.

Example 32 (7RS, 9aSR) -7- (4-Fluorophenoxy) methyl-2- (6-chloropyridazin-3-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (7RS, 9aSR) -7-hydroxymethyl-2,3,4,6,7,8,
A mixture of 9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (US Pat. No. 5,326,874) and 3,6-dichloropyrazine was combined according to Preparation Example 3. The product from this reaction was coupled with 4-fluorophenol according to Example 1 to give the title compound. mp (HCl) 255 ° C (decomposition). C ₁₉ H ₂₂ ClFN ₄ HRMS calcd for O: 376.1461; Found: 376.1458.

Example 33 (7RS, 9aSR) -7-phenoxymethyl-2- (6-chloropyridazin-3-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1 , 2-a] Pyrazine (7RS, 9aSR) -7-hydroxymethyl-2,3,4,6,7,8,
A mixture of 9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (US Pat. No. 5,326,874) and 3,6-dichloropyridazine was combined according to Preparation Example 3. The product from this reaction was coupled with phenol according to Example 1 to give the title compound. mp (.HCl)> 265 ° C (decomposition). C ₁₉ H ₂₃
HRMS Calcd for ClN ₄ O: 358.1555; Found: 358.1550.

Example 34 (7RS, 9aSR) -7-phenoxymethyl-2- (pyrimidin-4-yl) -2,3,4,6,7,8,9,9a-octahydro-1H
-Pyrido [1,2-a] pyrazine 0.110 g (0.307 mmol) of (7RS, 9aSR) -7-phenoxymethyl-2- (2-chloropyrimidin-4-yl)-
2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] A mixture of pyrazine (Example 29), 20 mg of 10% Pd / C and a few drops of concentrated hydrochloric acid in 30 mL ethanol was shaken under 50 psi of hydrogen gas at room temperature for 6 hours. The mixture was passed through celite and the liquid was evaporated. The residue was basified with concentrated ammonium hydroxide, extracted with chloroform, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with a solvent gradient of 100% chloroform to 95: 5 chloroform: methanol gave 0.020 g (20%) of the title compound. mp
(.HCl)> 265 ° C (decomposition). HRMS Calcd for _{C 19 H 24 N 4 O:} 324.1945; Found: 324.1970.

Example 35 (7RS, 9aSR) -7- (4-Fluorophenoxy) methyl-2- (pyridazin-3-yl) -2,3,4,6,7,8,9,9a-
Octahydro-1H-pyrido [1,2-a] pyrazine 0.150 g (0.363 mmol) of (7RS, 9aSR) -7- (4-fluorophenoxy) methyl-2- (6-chloropyridazin-3-yl) -2,3,4,6,7,8,9, 9a-octahydro-1H
-Pyrido [1,2-a] pyrazine (Example 32), 0.10 mL
(0.72 mmol) triethylamine and 20 mg of 10% Pd / C
Was shaken under 50 psi of hydrogen for 18 hours. The mixture was passed through celite and the liquid was evaporated. Dissolve the residue in chloroform, wash with water,
Dry (magnesium sulfate), filter, and evaporate.
mp (.HCl) 246-250 ° C. HRMS Calcd for _{C 19 H 23 FN 4 O:} 342.1851; Found: 342.1826.

Example 36 (7R, 9aS) -7- (3,5-difluorophenoxy) methyl-2- (6-chloropyridazin-3-yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (7R, 9aS) -N-BOC-7-hydroxymethyl-2,3,
4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a]
A mixture of pyrazine (WO 93/25552) and 3,5-difluorophenol is bound, followed by N-
BOC deprotected. The product from this reaction was coupled with 3,6-dichloropyridazine according to Preparation Example 3 to give the title compound. mp (.HCl) 254-259 ° C. ¹³ CNMR (base,
CDCl ₃ ): δ 26.7, 28.9, 36.1, 45.1, 50.4, 54.3, 58.4, 60.
3,71.4,96.3,95.0,98.4,115.2,128.8,146.8,158.8.

Example 37 (7R, 9aS) -7-phenoxymethyl-2- (6-chloropyridin-3-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1 , 2-a] Pyrazine (7R, 9aS) -N-BOC-7-hydroxymethyl-2,3,
4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a]
A mixture of pyrazine (WO 93/25552) and 3,5-difluorophenol is bound, followed by N-
BOC deprotected. The product from this reaction was coupled with 2,5-dichloropyridine according to Preparation Example 11 to give the title compound. mp (.HCl) 260-261 ° C. _{C 20 H 22 ClF 2 N 3} HRMS calcd for O: 393.1419; Found: 393.1410.

Example 38 3-[(7R, 9aS) -2-heteroaryl-2,3,4,6,7,8,
9,9a-octahydro-1H-pyrido [1,2-a] pyrazin-7-ylmethyl] -3H-benzoxazol-2-one The compound represented by the above formula was prepared according to Production Example 5 to give 3-
[(7R, 9aS) -2,3,4,6,7,8,9,9a-octahydro-1H-
Pyrido [1,2-a] pyrazin-7-ylmethyl] -3H-
Synthesized from benzoxazol-2-one (Preparation Example 12) and an appropriate heteroaryl chloride. Purification was generally achieved by flash silica gel chromatography using a mixture of ethyl acetate and hexane, or a mixture of chloroform and methanol as the eluting solvent. 2 shows melting points and high-resolution mass spectrum data of 2-substituents and monohydrochloride.

Example 38a _{2-(pyrimidin-2-yl); mp165~167 ℃; C 20 H} 23 N 5
HRMS Calcd for O _2: 365.1852; Found: 365.1850.

Example 38b 2- (5-fluoropyrimidin-2-yl); mp 170-17
1 ° C .; HRMS calculated for C ₂₀ H ₂₂ FN ₅ O ₂ : 383.1758; found:
383.1809.

Example 38c 2-(6- chloro-3-yl); mp176 _{(decomposition); C 20 H 22 ClN 5} HRMS Calcd for O _2: 399.1457; Found: 399.1519.

Example 39 3-[(7R, 9aS) -2- (5-chloropyridin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2 -A] pyrazin-7-ylmethyl] -3H-benzoxazol-2-one The title compound was prepared according to Preparation Example 11 by using 3-[(7R, 9aS)-
2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] Pyrazin-7-ylmethyl] -3H-benzoxazol-2-one (Preparation Example 12) and 2,5-dichloropyridine. mp (.HCl) 247-248 ° C. C ₂₁ H ₂₃ ClN
₄ HRMS Calcd for O _2: 398.1510; Found: 398.1484.

Example 40 (7RS, 9aSR) -7- (5-Fluorindol-1-yl) methyl-2- (pyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine The title compound was prepared according to Example 9 using (7RS, 9aSR) -7-
Hydroxymethyl-2- (pyrimidin-2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] It was synthesized from pyrazine (Production Example 3) and 5-fluoroindole. mp (.HCl) 70-72 ° C. C ₂₁ H ₂₅ FN ₅ (MH
HRMS calc for +): 366.2094; found: 366.2014.

Example 41 (7RS, 9aSR) -7- (4-Fluorophenylsulfanyl) methyl-2- (pyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine The title compound was prepared according to Example 1 using (7RS, 9aSR) -7-
Hydroxymethyl-2- (2-pyrimidin-2-yl)
-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2
-A] It was prepared from pyrazine (Production Example 3) and 4-fluorothiophenol. mp (.HCl) 99-101 ° C. C ₁₉ H ₂₃
HRMS calcd for FN ₄ S: 358.1627; Found: 358.1683.

Example 42 (7RS, 9aSR) -7- (4-Fluorophenylsulfonyl) methyl-2- (pyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine 0.50 g (1.40 mmol) of (7RS, 9aSR) -7- (4-fluorophenylsulfanyl) methyl-2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,9a- Octahydro-1H-
Pyrid [1,2-a] pyrazine (Example 41) and 1.13 g
A solution of (5.59 mmol) of 3-chloroperbenzoic acid in 30 mL of chloroform was stirred at room temperature for 20 hours. The solution was partitioned with 1M sodium hydroxide, the layers were separated, the organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 67:33 chloroform: methanol afforded 0.18 g (33%) of the title compound. mp (.HCl) 155-157 ° C. HRMS Calcd for _{C 19 H 23 FN 4 O 2} S: 390.1526; Found: 390.1483.

Example 43 (7R, 9aS) -7- (5-Fluorindol-1-yl) methyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,9, 9a-octahydro-1H-pyrido [1,2-a] pyrazine 6.0 g (22 mmol) of (7R, 9aS) -2-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (WO 93/25552) and 3.41 mL
A solution of (24.4 mmol) of triethylamine in 225 mL of dry methylene chloride was cooled to 0 ° C. and treated in 1.80 mL (23.3 mmol) of methanesulfonyl chloride in 75 mL of methylene chloride.
After stirring for 1 hour, add water and adjust the pH with 15% sodium hydroxide.
Was adjusted to 12. The layers were separated and the aqueous phase was extracted with methylene chloride. The combined organic phases are dried (magnesium sulfate), filtered and evaporated to give 7.73 g (100%) of (7R, 9a
S) -2-BOC-7- (methanesulfonyloxy) methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2
-A] provided pyrazine.

250 mL D of 8.41 g (62 mmol) of 5-fluoroindole
The MF solution was treated with 2.46 g (62 mmol) of sodium hydride (60% oil dispersion) and the mixture was stirred at 50 ° C. for 1.5 hours. Heating was suspended and 7.73 g (22.2 mmol) of (7R, 9a
S) -2-BOC-7- (methanesulfonyloxy) methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2
-A] A 250 mL DMF solution of pyrazine was added and the mixture was stirred at 100 ° C for 2 hours. The mixture was cooled to room temperature, diluted with water, acidified to pH 2 with 6M hydrochloric acid and washed with ethyl acetate. The aqueous phase is made basic to pH 12 with concentrated ammonium hydroxide,
Extracted with ethyl acetate (3x). The combined organic phases were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with ethyl acetate gave 3.09 g (36%) of (7R, 9aS) -2-BOC-7-
(5-fluoroindol-1-yl) methyl-2,3,4,
6,7,8,9,9a-Octahydro-1H-pyrido [1,2-a] pyrazine was provided.

3.0 g (7.75 mmol) of (7R, 9aS) -2-BOC-7- (5
-Fluoroindol-1-yl) methyl-2,3,4,6,7,
200 mL of 8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine in 70:30 trifluoroacetic acid: water solution at room temperature in 1 mL
Stirred for hours. The mixture was concentrated in vacuo, basified with 15% sodium hydroxide and extracted with ethyl acetate (2x).
The combined organics were dried (magnesium sulfate), filtered and evaporated to give 2.0 g (90%) of (7R, 9aS) -7-.
(5-fluoroindol-1-yl) methyl-2,3,4,
6,7,8,9,9a-Octahydro-1H-pyrido [1,2-a] pyrazine was provided.

2.20 g (7.67 mmol) of (7R, 9aS) -7- (5-fluoroindol-1-yl) methyl-2,3,4,6,7,8,9,9a-
Octahydro-1H-pyrido [1,2-a] pyrazine, 1.02 g
A 100 mL water mixture of (7.67 mmol) of 2-chloro-5-fluoropyrimidine and 1.98 g (18.4 mmol) of sodium carbonate was stirred at 95 ° C for 72 hours. Cool the mixture to room temperature,
Extract with chloroform (3x), wash the combined organic phases with brine, dry (magnesium sulfate), filter,
Evaporated. Purification by flash silica gel chromatography with 50:50 ethyl acetate: hexane gave 1.17.
This gave g (40%) of the title compound. mp (HCl) 180-182
° C. HRMS Calcd for _{C 21 H 23 F 2 N 5} : 383.1922; Found: 3
83.1924.

Example 44 1-[(7R, 9aS) -2- (pyrimidin-2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] Pyrazin-7-ylmethyl] -1,3-dihydroindol-2-one 6.0 g (22 mmol) of (7R, 9aS) -2-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (WO 93/25552) and 3.41 mL
A solution of (24.4 mmol) of triethylamine in 225 mL of dry methylene chloride was cooled to 0 ° C. and treated in 1.80 mL (23.3 mmol) of methanesulfonyl chloride in 75 mL of methylene chloride.
After stirring for 1 hour, add water and adjust the pH with 15% sodium hydroxide.
Was adjusted to 12. The layers were separated and the aqueous phase was extracted with methylene chloride. The combined organic phases are dried (magnesium sulfate), filtered and evaporated to give 7.73 g (100%) of (7R, 9a
S) -2-BOC-7- (methanesulfonyloxy) methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2
-A] provided pyrazine.

A solution of 2.75 g (10.7 mmol) of oxindole in 85 mL of DMF was treated with 0.82 g (21 mmol) of sodium hydride (60% oil dispersion) and the mixture was stirred at 50 ° C. for 1.5 hours.
Heating was suspended and 2.56 g (7.38 mmol) of (7R, 9aS)-
2-BOC-7- (methanesulfonyloxy) methyl-2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a) Add 85 mL of pyrazine in DMF and bring the mixture to 100 ° C for 2 hours.
Stirred for hours. The mixture was cooled to room temperature, diluted with water,
The mixture was acidified to pH 2 with 6M hydrochloric acid, and washed with ethyl acetate. The aqueous phase was basified to pH 12 with concentrated ammonium hydroxide and extracted with ethyl acetate (3x). The combined organic phases were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with ethyl acetate yielded 0.677 g (24%) of 1-[(7R, 9aS) -2-BOC-2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazin-7-ylmethyl] -1,3-dihydro-indol-2-one.

0.53 g (1.38 mmol) of 1-[(7R, 9aS) -2-BOC-2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] Pyrazin-7-ylmethyl] -1,3-dihydro-indol-2-one in 10 mL of chloroform was treated with excess HCl (g) in ethyl ether and stirred at room temperature for 1 hour. After evaporation of the solvent, 0.49 g (100%) of 1-
[(7R, 9aS) -2,3,4,6,7,8,9,9a-octahydro-1H-
Pyrido [1,2-a] pyrazin-7-ylmethyl] -1,3-
Dihydro-indol-2-one.2HCl was provided.

0.49 g (1.38 mmol) of 1-[(7R, 9aS) -2,3,4,6,7,
8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazin-7-ylmethyl] -1,3-dihydro-indole-
20 m of 2-one.2HCl, 0.157 g (1.37 mmol) of 2-chloropyrimidine and 0.64 g (6.02 mmol) of sodium carbonate
The L water mixture was stirred at 95 ° C for 16 hours. The mixture was cooled to room temperature, extracted with chloroform (3x), the combined organic phases were washed with brine, dried (magnesium sulfate),
And evaporated. Purification by flash silica gel chromatography with 95: 5 ethyl acetate: methanol afforded 0.181 g (30%) of the title compound. mp (・ HC
l) 174-176 ° C. HRMS Calcd for _{C 21 H 25 N 5 O:} 363.205
9; Found: 363.2032.

Example 45 (7RS, 9aSR) -7-phenoxy-2- (pyrimidine-2
-Yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine 0.600 g (3.03 mmol) of (9aSR) -7- (ethylenedioxy) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (Compwernolle) , F; Slaeh, MA; Top
pet, S .; Hoornaert G .; J. Org. Chem., 1991, 56, 5192), 0.
35 g (3.0 mmol) of 2-chloropyrimidine and 0.77 g
A 6 mL solution of (7.3 mmol) sodium carbonate was refluxed for 21 hours. The mixture was cooled to room temperature, extracted with methylene chloride (3x), the combined organic phases were washed with water and brine,
Dry (magnesium sulfate), filter, and evaporate.
Purification by flash through a 30 g plug of flash silica gel with 95: 5 ethyl acetate: ethanol gave 0.624 g (75
%) Of (9aSR) -7- (ethylenedioxy) -2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2 -A] provided pyrazine. mp (base) 121-122 ° C. Calcd for _{C 14 H 20 N 4 O 2} : C, 6
0.85; H, 7.29; N, 20.27; Found: C, 60.84; H, 7.26; N, 20.4
2.

0.60 g (2.2 mmol) of (9aSR) -7- (ethylenedioxy) -2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,
A solution of 9a-octahydro-1H-pyrido [1,2-a] pyrimidine was dissolved in 8 mL of 6M HCl and refluxed for 3 hours. Cool the solution to room temperature, evaporate the solvent, dissolve the residue in methylene chloride, mix with aqueous potassium carbonate, separate the layers,
The aqueous layer was extracted with methylene chloride (2x). The combined organic phases were dried (magnesium sulfate), filtered and evaporated.
Filtration through a plug of flash silica gel with 95: 5 ethyl acetate: ethanol gave 0.205 g (41%) of the 7-keto derivative. The 7-keto derivative was dissolved in 10 mL of methanol and treated with 0.33 g (0.88 mmol) of 10% sodium borohydride on alumina. After stirring for 1 hour, the mixture was filtered and evaporated to give 0.156 g (75%) of crude 7
To give the hydroxy derivative. Crude 7-hydroxy derivative, 0.094 g (1.0 mmol) phenol and 0.209 g
(0.799 mmol) of triphenylphosphine in 1.4 mL of dried
Dissolved in THF. The mixture was treated with 0.13 mL (0.80 mmol) of diethyl azodicarboxylate and stirred at room temperature for 24 hours. Dilute the mixture with ethyl ether and add 0.1 M HCl (3
x), the combined aqueous phases were extracted with ethyl ether (2x), basified with concentrated ammonium hydroxide and extracted with ethyl acetate (3x). The combined ethyl acetate layers were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 50:50 ethyl acetate: hexane provided 0.036 g (17%) of the title compound. mp (base) 147-148 ° C. HRMS Calcd for _{C 18 H 22 N 4 O:} 310.1794; Found: 310.1819.

Example 46 (4-Fluorophenyl)-[(7RS, 9aSR) -2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1 , 2-a] Pyrazin-7-yl] -methanol Attach the flame-dried 3-diameter flask to the bleach trap, and add 20 mL of methylene chloride and 0.77 mL (1.1 mmo).
l) was charged with oxalyl chloride. Solution at -78 ° C
At a rate that keeps the internal temperature below -50 ° C.
SO (1.38 mL, 1.93 mmol) was added dropwise. (7RS, 9aSR) -7
-Hydroxymethyl-2- (pyrimidin-2-yl)-
2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] A solution of pyrazine (2.5 g, 9.1 mmol) in methylene chloride was added, followed by the slow addition of 5.2 mL (37 mmol) of triethylamine. After warming to room temperature, 40 mL of water was added, the layers were separated, and the aqueous phase was extracted with methylene chloride (4x). The combined organic phases are dried (magnesium sulfate) and filtered,
Evaporation gave 2.24 g (90%) of the aldehyde.
¹³ CNMR (CDCl ₃ ): δ24.0, 28.5, 43.5, 48.8, 49.0, 55.4, 5
4.7,60.3,109.9,157.7,161.3,202.3. HRMS Calcd for _{C 13 H 18 N 4 O:} 246.1481; Found: 246.1484.

A 45 mL solution of the crude aldehyde (0.44 g, 1.6 mmol) in dry THF was cooled to -10 ° C. and 8.8 mL (18 mmol, 2 M in THF) of 4-
Treated with fluorophenyl magnesium bromide.
The solution was warmed to room temperature, 10 mL of ice water was added, followed by 100 m
L saturated ammonium chloride was carefully added. Extract the aqueous phase with ethyl ether (1x) and (with magnesium sulfate)
Dry, pass and evaporate. Purification by flash silica gel chromatography with methylene chloride: methanol: concentrated ammonium hydroxide 12: 1: 0.04 yielded 0.037 g (6.
(7%) of the title compound. ¹³ C NMR (CDCl ₃ ): δ 26.
1,28.8,43.2,43.3,46.1,48.8,54.8,57.8,58.0,60.9,76.
4,109.9,115.09,115.38,127.98,128.09,138.7,157.7,16
0.6,161.4,163.4. C ₁₉ H ₂₄ FN ₄ HRMS calcd for O (MH +): 343.1934; Found: 343.1938.

Example 47 (4-Fluoro) phenyl-[(7SR, 9aSR) -2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1 , 2-a] Pyrazin-7-yl] -methanol The title compound was prepared according to Example 46, using (7SR, 9aSR) -7-
Hydroxymethyl-2- (pyrimidin-2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a) Prepared starting with pyrazine. C ₁₉ H ₂₄ FN ₄ O (MH +)
HRMS calc for: 343.1934; found: 343.1934.

Example 48 (4-Fluoro) phenyl-[(7RS, 9aSR) -2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1 , 2-a] Pyrazin-7-yl] -methanone The title compound is the oxalyl chloride of Example 46 / DMSO
According to the oxidation step, (4-fluoro) phenyl [(7RS, 9a
SR) -2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,
9a-octahydro-1H-pyrido [1,2-a] pyrazine-
7-yl] -methanol (Example 46). ¹³ C NMR (CDCl ₃ ): δ 27.3, 28.3, 48.6, 54.1, 56.7, 5
9.9,110.1,115.77,116.05,131.20,131.32,132.4,158.0,
161.1, 163.4, 166.7. HRMS Calcd for _{C 19 H 21 FN 4 O:} 34
0.1699; Found: 340.1539.

Example 49 (7S, 9aS) -7- (4-Fluorophenoxy) methyl-
2- (5-fluoropyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine 0.82 g (3.08 mmol) of (7S, 9aS) -7-hydroxymethyl-2- (5-fluoropyrimidin-2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] Pyrazine (Production Example 13), 0.52 g (4.62 mmol) of 4-
A solution of fluorophenol, 0.97 g (3.70 mmol) of triphenylphosphine in dry THF was treated with 0.64 g (3.70 mmol) of diethyl azodicarboxylate and stirred at room temperature for 72 hours. Evaporate the solvent and remove the residue with 50:50 ethyl acetate:
Dissolved in ethyl ether and treated with HCl (g) in ethyl ether until precipitation ceased. Upon filtration, the solid was collected, dissolved in chloroform, 1 M sodium hydroxide was added, and the layers were separated. The organic layer was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 90:10 hexane; ethyl acetate gave 0.49 g (44%) of the title compound. mp
(.HCl) 225-228 ° C. ¹³ C NMR (base, CDCl ₃ ): δ 24.
8,25.2,33.8,44.3,49.7,54.8,56.6,61.0,69.5,115.48,1
15.53,115.59,115.83,144.97,145.26,149.85,153.15,15
5.42,155.54,158.69,158.74. HRMS for _{C 19 H 22 F 2 N 4} O
Calculated: 360.1762; Found: 360.1752.

Example 50 (7RS, 9aSR) -7- (5-Fluoro-1H-indole-3
-Yl) methyl-2- (pyrimidin-2-yl) -2,3,
4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a]
Pyrazine 2.22 g (8.1 mmol) of (7RS, 9aSR) -7-hydroxymethyl-2- (2-pyrimidinyl) -2,3,4,6,7,8,9,9a-
Octahydro-1H-pyrido [1,2-a] pyrazine (Preparation Example 3) and triethylamine (1.34 mL, 9.7 mmol)
The methylene chloride solution was cooled to 0 ° C., and 0.64 mL (8.3 mmo
l) Methanesulfonyl chloride was treated with 7 mL of methylene chloride solution. The solution was stirred at 0 ° C. for 1 hour, then
Warmed to room temperature. Water (30 mL) was added and the pH was adjusted to 9.5 with 2M sodium hydroxide. The layers were separated and the aqueous phase was extracted with methylene chloride (30mL). Dry the combined organic phases (over sodium sulfate), filter and evaporate to 2.05 g (78
%) Of the mesylate.

0.2 g (1.5 mmol) of 5 in a flame-dried flask
-Fluorindole, 8 mL benzene and 0.49 mL
(1.5 mmol) of ethyl magnesium bromide (3 in THF
M). The above mesylate (0.53
g, 1.6 mmol) and the mixture was stirred at room temperature for 18 hours.
Water (15 mL), ethyl acetate (10 mL) and saturated sodium bicarbonate were added and the layers were separated. The organic phase was dried (over sodium sulfate), filtered and evaporated. Initial purification by flash silica gel chromatography with 95: 5 ethyl acetate: methanol followed by a second purification by flash silica gel chromatography with 30: 70: 2 ethyl acetate: hexane: methanol gives 80 mg of the title compound. Was. ¹³ C NMR (CDCl ₃ ): δ 29.5, 30.2, 30.8, 37.1, 43.6,
49.1,54.8,60.9,103.8,104.1,109.0,109.4,109.8,110.
7,110.9,114.4,114.5,123.7,132.8,156.1,157.7,159.2,
161.5. HRMS Calcd for _{C 21 H 24 FN 5: 365.2011} ; Found: 365.1985.

Example 51 (7RS, 9aSR) -7- (5-Fluoro-1-methyl-1H-
Indole-3-yl) methyl-2- (pyrimidine-2
-Yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine 0.103 g (0.28 mmol) of (7RS, 9aSR) -7- (5-fluoro-1H-indole-
3-yl) methyl-2- (pyrimidin-2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine (Example 50), anhydrous DMF (1 mL) and 12 mg
(0.30 mmol) of sodium hydride (60% dispersion). The suspension was treated with 0.019 mL (0.31 mmol) of methyl iodide and the mixture was heated to 50 ° C. for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, diluted with methylene chloride (25mL) and water (25mL) and the layers were separated. The organic phase was dried (over sodium sulfate), filtered and evaporated to a solid residue. The solid was washed with ethyl acetate (2x) and the ethyl acetate was evaporated to give 50 mg of the title compound. ¹ HNMR
(CDCl ₃ ): δ1.00-1.31 (m, 3H), 1.64-2.23 (m, 6
H), 2.54-3.1 (m, 5H), 3.69 (s, 3H), 4.51-4.56 (m.,
2H), 6.43 (Dd, J = 1Hz, 1H), 6.83 (s, 1H), 6.93 (m, 1
H), 7.15 (m, 2H), 8.27 (d, J = 1 Hz, 2H). TLC; Rf: 0.81
(90: 10: 1 methylene chloride: methanol: ammonium hydroxide).

Example 52 (7RS, 9aSR) -7- (5-chloro- and-(6-chloro-2-methyl-benzimidazol-1-yl) methyl-2- (pyrimidin-2-yl) -2,3, 4,6,7,8,9,9a
-Octahydro-1H-pyrido [1,2-a] pyrazine 2.22 g (8.1 mmol) of (7RS, 9aSR) -7-hydroxymethyl-2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,
9a-octahydro-1H-pyrido [1,2-a] pyrazine (Production Example 3) and triethylamine (1.34 mL, 9.7 mmol)
l) is cooled to 0 ° C in 15 mL of methylene chloride solution, and 0.64 mL
(8.3 mmol) of methanesulfonyl chloride in 7 mL of methylene chloride. The solution was stirred at 0 ° C. for 1 hour and then warmed to room temperature. Water (30 mL) was added and the pH was adjusted to 9.5 with 2M sodium hydroxide. The layers were separated and the aqueous phase was extracted with methylene chloride (30mL). The combined organic phases are dried (sodium sulfate), filtered and evaporated,
2.05 g (78%) of the mesylate was given.

In a flame-dried flask, 0.11 g (0.67 mmol) of 5-chloro-2-methylbenzimidazole, 3 mL of dry DMF and 29 mg (0.74 mmol) of sodium hydride (60
% Oil dispersion). The solution was heated to 50 ° C. for 30 minutes and then cooled to room temperature. The above mesylate (0.20
g, 0.61 mmol) was added and the mixture was heated to 100 ° C. for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate (30 mL) and water (30 mL) were added, the layers were separated, the organic phase was dried (over sodium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with ethyl acetate gave 130 mg of a mixture of the title compounds. ¹ H NMR (CDCl ₃ ): δ 1.2 (m, 2H), 1.9 (m, 5 H), 2.
2 (m, 2H), 2.5 (s, 3H), 2.75 (m, 2H), 2.95 (m, 1H), 3.
85 (m, 2H), 4.55 (m, 2H), 6.45 (dd, J = 1Hz, 1H), 7.1
(S, 1H) ,, 7.2 (m, 1H), 7.4 (m, 1H), 8.25 (d, J = 1Hz, 2
H). TLC; Rf: 0.32 (90:10 methylene chloride: methanol). HRMS Calcd for _{C 21 H 25 ClN 6: 396.1829} ; Found: 396.1809.

Example 53 1- (4-Fluorophenyl) -2-[(7RS, 9aSR)-
2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazin-7-yl] -ethanol 2.2 g (8.1 mmol) of (7RS, 9aSR) -7-hydroxymethyl-2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,
A 0 ° C. solution of 9a-octahydro-1H-pyrido [1,2-a] pyrazine and 1.3 mL (9.7 mmol) of triethylamine in 15 mL of methylene chloride is treated with 0.64 mL (8.3 mmol) of methanesulfonyl chloride in 7 mL of methylene chloride. And the solution was stirred for 1 hour. Water (30 mL) was added and the pH was adjusted to 9.5 with 2M sodium hydroxide. The layers were separated, the aqueous phase was extracted with methylene chloride (30 mL), the combined organic phases were dried (over sodium sulfate), filtered and evaporated to give 2.05 g (7
8%) of mesylate.

The above mesylate (2.05 g, 6 mmol) was dissolved in 50 mL of dry DMF, 0.31 g (6 mmol) of sodium cyanide was added, and the mixture was heated to 110 ° C. for 16 hours under a nitrogen atmosphere. The reaction was cooled to room temperature and 1 mL of saturated sodium carbonate solution was added. The solvent was removed under reduced pressure, and the residue was treated with ethyl acetate (100 m
L) and water (50 mL) and the layers were separated. The organic layer was washed with saturated sodium carbonate (2x), dried (over sodium sulfate), filtered and evaporated to give 1.4 g (91%) of the nitrile. HRMS Calcd for C ₁₄ H ₁₉ N _5: 257.164
0; found: 257.1630.

A flame-dried flask containing 0.350 g (1.36 mmol) of the above nitrile was charged with 1.8 mL (1.8 mmol) of 1 M diisobutylaluminum hydride. The solution was stirred at room temperature for 2 hours, then at 50 ° C. for 1 hour. The reaction was cooled to room temperature and 2M hydrochloric acid was added slowly until gas evolution ceased. The pH was adjusted to 8 with 2M sodium hydroxide and the mixture was diluted with 50 mL of ethyl ether and 50 mL of water. Separate the layers and separate the organic phase (with sodium sulfate)
Dry, pass and evaporate. Purification by flash silica gel chromatography with 18: 1: 0.04 methylene chloride: methanol: concentrated ammonium hydroxide gave 31 mg (9
%) Aldehyde.

A flame-dried flask containing 30 mg (0.10 mmol) of the above aldehyde in 1 mL of dry THF was cooled to −10 ° C. and 0.075 mL (0.15 mmol) of 4-fluorophenylmagnesium bromide (2M in THF) was added. The reaction was warmed to room temperature and stirred for 1 hour. Water (1 mL), saturated ammonium chloride (1 mL) and ethyl ether (5 mL) were added, and the phases were separated. The organic phase was dried (over sodium sulfate), filtered and evaporated. 24: 1: 0.04 methylene chloride:
Purification by flash silica gel chromatography with methanol: concentrated ammonium hydroxide yields 11 mg (39%)
To give the title compound. ¹ H NMR (CDCl ₃ ): δ 0.97-1.05
(M, 1H), 1.23-1.61 (m, 2H), 1.64-1.86 (m, 6H), 2.1
4−2.23 (m, 1H), 2.54−2.78 (m, 1H), 2.81−3.02 (m, 3
H), 4.49−4.61 (m, 2H), 4.77−4.71 (m, 1H), 6.45 (t,
J = 1Hz, 1H), 6.97-7.03 (m, 2H), 7.25-7.32 (m, 2H),
8.27 (d, J = 1 Hz, 2H). HRMS Calcd for C ₂₀ H ₂₅ FN ₄ O:
356.2012; Found: 356.2009.

Example 54 1- (4-Fluorophenyl) -2-[(7SR, 9aSR)-
2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazin-7-yl] -ethanone 38.1 g (117 mmol) of (7SR, 9aSR) -7- (methanesulfonyloxy) methyl-2- (pyrimidin-2-yl)
-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2
-A] 50% of pyrazine (prepared according to US Patent 5,122,525) and 6.01 g (122 mmol) of sodium cyanide.
The 0 mL dry DMF solution was heated to 110 ° C. for 16 hours. The mixture was cooled to room temperature and 10 mL of saturated sodium bicarbonate was added,
The mixture was concentrated under reduced pressure. Water (1000 mL) and ethyl acetate (1000 mL) were added to the solid residue, the pH was adjusted to 11, and the layers were separated. The organic phase was washed with water (2x), dried (sodium sulfate), filtered and evaporated. Recrystallization from ethyl acetate-hexane gave 14.5 g of [(7SR, 9aSR) -2-
(Pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazin-7-yl]
Acetonitrile was provided. ¹³ CNMR (CDCl ₃ ): δ19.5,2
4.1, 26.9, 31.3, 33.1, 43.6, 48.9, 54.5, 109.8, 119.8, 157.
7,161.7.

0.200 g (0.78 mmol) of [(7SR, 9aSR) -2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-
A solution of 1H-pyrido [1,2-a] pyrazin-7-yl] acetonitrile in 4 mL of dry THF was obtained by adding 4.3 mg (0.03 mmol) of cuprous bromide and 0.85 mL (0.85 mmol) of 4-fluorophenylmagnesium bromide ( (1M in THF) and the mixture was refluxed for 48 hours. The mixture was cooled to room temperature and 0.75 mL of water was carefully added, followed by 3.5 mL of 15% sulfuric acid. The mixture was refluxed for 24 hours. The reaction was cooled to room temperature and 10% sodium carbonate solution was added until gas evolution ceased. Ethyl ether (10 mL) was added, the layers were separated,
The aqueous phase was extracted with ethyl ether (2x10mL). The combined organics were dried (over sodium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with ethyl acetate: hexane: methanol: concentrated ammonium hydroxide (1: 1: 0.01: 0.01) gave 30 mg of the title compound. ¹³ C NMR (CDCl ₃ ): δ 25.1, 28.3, 29.9, 40.2, 4
3.7,49.1,54.8,59.1,61.1,109.7,115.4,115.7,130.8,13
0.9,134.0,157.7,161.5,164.0,167.4. HRMS Calcd for _{C 20 H 23 FN 4 O:} 354.1856; Found: 354.1847.

Example 55 (7S, 9aS) -7- (Substituted-phenoxy) methyl-2-
(5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,
9,9a-octahydro-1H-pyrido [1,2-a] pyrazines The compound represented by the above formula was prepared according to Example 49 (7S, 9
aS) -7-Hydroxy) methyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] Prepared using pyrazine (Preparation Example 13) and the appropriate phenol. Purification was generally achieved by flash silica gel chromatography using a mixture of ethyl acetate and hexane as the eluting solvent. The stereochemical configuration, 7- (substituted-phenoxy) methyl substituent, melting point of monohydrochloride and HRMS data are shown.

Example 55a (7S, 9aS) -7- (4-fluoro-2-methyl-phenoxy) methyl; mp 237-243 ° C. HRM for C ₂₀ H ₂₄ F ₂ N ₄ O
S Calculated: 374.1913; Found: 374.1874.

Example 55b (7S, 9aS) -7- (3-cyano-phenoxy) methyl-; mp 209-211 ° C. C ₂₀ H ₂₃ FN ₅ HRMS calcd for O (MH +): 368.1887; Found: 368.1884.

Example 55c (7S, 9aS) -7- [ 3- ( carbomethoxy) methyl - phenoxy] _{-; mp158~161 ℃; C 22 H} 28 FN 4 O 3 (MH
HRMS calculated for +): 415.2139; found: 415.2123.

Example 56 (7S, 9aS) -7- (Substituted-phenoxy) methyl-2-
(5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,
9,9a-octahydro-1H-pyrido [1,2-a] pyrazines The following compounds were prepared according to Example 8 using (7S, 9aS) -7-
Hydroxy) methyl-2- (5-fluoropyrimidine-
2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (Preparation Example 13) and an appropriate phenol. Purification was generally achieved by flash silica gel chromatography using a mixture of ethyl acetate and hexane or a mixture of chloroform and methanol as the eluting solvent. Stereochemical configuration, a 7- (substituted-phenoxy) methyl substituent,
Figure 3 shows the melting point and HRMS data for monohydrochloride.

Example 56a (7S, 9aS) -7- (4-fluoro-2-trifluoromethylphenoxy) methyl; mp 205-206 ° C. HRMS Calcd for _{C 20 H 21 F 5 N 4} O: 428.1636; Found: 428.1633.

Example 56b (7S, 9aS) -7- (2-bromo-4-fluorophenoxy) methyl; mp 228-230 ° C. HRMS for C ₁₉ H ₂₁ BrF ₂ N ₄ O
Calculated: 438.0867; Found: 438.0862.

Example 56c (7S, 9aS) -7- ( 2- carbomethoxy-4-fluorophenoxy) methyl; mp204~205 ℃; HRMS calcd for _{C 21 H 24 F 2 N 4} O 3: 418.1816; Found: 418.1836 .

Example 56d (7S, 9aS) -7- ( 3,4- difluorophenoxy) methyl _{-; mp226~227 ℃; C 19 H} 21 F 3 N 4 HRMS calcd for O: 37
8.1667; found: 378.1640.

Example 56e (7S, 9aS) -7- ( 3,5- difluorophenoxy) methyl _{-; mp208~211 ℃; C 19 H} 21 F 3 N 4 HRMS calcd for O: 37
8.1667; found: 378.1703.

Example 56f (7S, 9aS) -7- ( 3- trifluoromethoxy-phenoxy) methyl _{-; mp180~184 ℃; C 20 H} 23 F 4 N 4 O 2 HRMS calcd for (MH +): 427.1757; Found: 427.1776.

Example 56g (7S, 9aS) -7- ( 4- trifluoromethylphenoxy) methyl _{-; mp188~193 ℃; C 20 H} 23 F 4 N 4 HRMS calcd for O (MH +): 411.1803; Found: 411.1803 .

Example 56h (7S, 9aS) -7- ( 3- methoxyphenoxy) methyl _{-; mp229~103 ℃; C 20 H} 26 FN 4 O 2 HRMS calcd for (MH +): 373.2040; Found: 373.2051.

Example 56i (7S, 9aS) -7- ( 4- methoxyphenoxy) methyl _{-; mp220~224 ℃; C 20 H} 26 FN 4 O 2 HRMS calcd for (MH +): 373.2040; Found: 373.2055.

Example 56j (7S, 9aS) -7- (4-ethylphenoxy) methyl-; m
p227-229 ° C; HRMS calculated for C ₂₁ H ₂₈ FN ₄ O (MH +): 3
71.2247; found: 371.2228.

Example 56k (7S, 9aS) -7- ( 2,4- difluorophenoxy) methyl _{-; mp222~224 ℃; C 19 H} 22 F 3 N 4 HRMS for O (MH +)
Calculated: 379.1746; Found: 379.1759.

Example 56l (7S, 9aS) -7- (4-carboethoxy-phenoxy)
Methyl-; mp 230-232 ° C; H to C ₂₂ H ₂₈ FN ₄ O ₃ (MH +)
RMS calc: 415.2145; found: 415.2130.

Example 56m (7S, 9aS) -7- ( 4- bromo-2-methoxy - phenoxy) methyl _{-; mp214~216 ℃; C 20 H} 25 BrFN 4 O 2 (MH +)
HRMS calc for: 451.1145; found: 451.1108.

Example 56n (7S, 9aS) -7- ( 3,4,5- trifluoro - phenoxy) methyl _{-; mp188~191 ℃; C 19 H} 21 F 4 N 4 HRMS calcd for O (MH +): 397.1651; Found: 397.1667.

Example 56o (7S, 9aS) -7- ( 3- nitro - phenoxy) methyl _{-; mp114~119 ℃; C 19 H} 23 FN 5 O 3 (MH +) for HRMS calcd: 388.1785; found 388.1799.

Example 56p (7S, 9aS) -7- ( 3- acetamido - phenoxy) methyl _{-; mp162~165 ℃; C 21 H} 27 FN 5 O 2 HRM for (MH +)
S Calculated: 400.2149; Found: 400.2131.

Example 56q (7S, 9aS) -7- ( 3- trifluoromethyl - phenoxy) methyl _{-; mp200~202 ℃; C 20 H} 23 F 4 N 4 HRMS calcd for O (MH +): 411.1801; Found: 411.1781.

Example 56r (7S, 9aS) -7- (3-carbomethoxy-phenoxy)
Methyl-; mp 225-226 ° C; H to C ₂₁ H ₂₆ FN ₄ O ₃ (MH +)
RMS calc: 401.1989; found: 401.1989.

Example 56s (7S, 9aS) -7- [ 3- (4- morpholino) - phenoxy] _{-; mp233~236 ℃; C 23 H} 31 FN 5 O 2 HRMS calcd for (MH +): 428.2462; measured value : 428.2477.

Example 56t (7S, 9aS) -7- [ 3- (1,1- dimethyl) ethyl - phenoxy] _{-; mp252~254 ℃; C 23 H} 32 FN 4 O (MH +)
HRMS calcd for: 399.2560; found: 399.2528.

Example 56u (7S, 9aS) -7- ( 4- fluoro-2-propyl - phenoxy) methyl _{-; mp165~170 ℃; C 22 H} 28 F 2 N 4 O (MH +)
HRMS calculated for: 402.2225; found: 402.2183.

Example 56v (7S, 9aS) -7- ( 3- methyl - phenoxy) methyl _{-; mp90~92 ℃; C 20 H} 26 FN 4 HRMS calcd for O (MH +): 357.2091; Found: 357.2088.

Example 56w (7S, 9aS) -7- (3-dimethylamino-phenoxy)
Methyl -; mp216~220 ℃ _{(decomposition); C 21 H 29 FN 5} HRMS calcd for O (MH +): 386.2356; Found: 386.2368.

Example 56x (7S, 9aS) -7- [2-methoxy-3- (1-methyl)
Ethyl-phenoxy] methyl-; mp 221-223 ° C (decomposition);
_{C 23 H 32 FN 4 O 2} HRMS calcd for (MH +): 415.2505; Found: 415.2467.

Example 56y (7S, 9aS) -7- ( 4- acetamido - phenoxy) methyl _{-; mp220~223 ℃; C 21 H} 27 FN 5 O 2 HRM for (MH +)
S Calculated: 400.2143; Found: 400.2136.

Example 57 (7S, 9aS) -7- (Substituted-phenoxy) methyl-2-
(5-chloropyridin-2-yl) -2,3,4,6,7,8,9,9a
-Octahydro-1H-pyrido [1,2-a] pyrazines The compound represented by the above formula was prepared according to Example 8 (7S, 9
aS) -7-Hydroxymethyl-2- (5-chloropyridin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H
-Pyrido [1,2-a] pyrazine (Preparation Example 14) and an appropriate phenol. Purification generally involves the use of a mixture of ethyl acetate and hexane as the elution solvent, or
Achieved by flash silica gel chromatography using a mixture of chloroform and methanol. The stereochemical configuration, 7- (substituted-phenoxy) methyl substituent, melting point of monohydrochloride and HRMS data are shown.

Example 57a (7S, 9aS) -7- (4-Fluorophenoxy) methyl: m
p244-249 ° C. HRMS Calcd for _{C 20 H 23 ClFN 3 O:} 375.15
08; found: 375.1490.

Example 57b (7S, 9aS) -7- (3,5-difluorophenoxy) methyl: mp 230-233 ° C. _{C 20 H 22 ClF 2 N 3} HRMS calcd for O: 3
93.1414; Found: 393.1389.

Production Example 1 (7R, 9aS) -7-hydroxymethyl-2,3,4,6,7,8,9,9a
-Octahydro-1H-pyrido [1,2-a] pyrazine · 2HC
l 4.0 g (15 mmol) of (7R, 9aS) -2-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine A solution of (WO 93/25552) in 40 mL chloroform was treated with excess HCl (g) in ether.
After stirring for 1 hour, the solvent was evaporated to give 3.1 g (86%) of a hygroscopic dihydrochloride, which was used without further purification in the subsequent reaction. ¹³ CNMR (2HCl, d-6DMS
O): δ26.9, 28.8, 30.5, 44.9, 50.6, 54.7, 59.0, 61.1, 64.
Five. C ₉ H ₁₈ N ₂ HRMS calcd against the O: 170.1419; Found: 170.14
14.

Production Example 2 (7S, 9aS) -7-hydroxymethyl-2,3,4,6,7,8,9,9a
-Octahydro-1H-pyrido [1,2-a] pyrazine 5.84 g (21.6 mmol) of (7S, 9aS) -N-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-
A solution of pyrido [1,2-a] pyrazine (WO 93/25552) in 140 mL of trifluoroacetic acid and 60 mL of water were stirred at room temperature for 16 hours. The mixture was concentrated and the residue was dissolved in water. The aqueous phase was saturated with solid sodium carbonate and extracted with chloroform (3x). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to give 3.39 g (92%) of the title compound. This material was used for subsequent reactions without further purification. ¹³ C NMR (base, d-6 DMSO): δ 24.
8,25.1,36.0,45.7,51.9,56.1,56.7,62.0,62.7.

Production Example 3 (7RS, 9aSR) -7-hydroxymethyl-2- (pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H
-Pyrido [1,2-a] pyrazine 4.5 g (26 mmol) of (7RS, 9aSR) -7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,
2-a] pyrazine (U.S. Pat. No. 5,326,874), 3.0 g (26 mmo
A 100 mL water mixture of 1) 2-chloropyrimidine and 6.7 g (63 mmol) of sodium carbonate was heated to 95 ° C. for 16 hours. The mixture was cooled to room temperature, extracted with methylene chloride (3x), the combined organic layers were washed with water and brine, dried, filtered and evaporated to give 4.68g (72%) of the title compound, It was used for subsequent reactions without further purification.

Production Example 4 (7R, 9aS) -7-hydroxymethyl-2,3,4,6,7,8,9,9a
-Octahydro-2- (pyrimidin-2-yl) -1H-
Pyrido [1,2-a] pyrazine 2.52 g (14.8 mmol) of (7R, 9aS) -7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (Production Example 1), 1.70 g (14.8 mmol)
Of 2-chloropyrimidine and 6.91 g (65.2 mmol) of sodium carbonate in a 150 mL water mixture was heated to 90 ° C. for 16 hours,
It was then cooled and extracted with chloroform (3x). The organic layer was dried (magnesium sulfate), filtered and evaporated to give 3.25 g (89%) of the title compound, which was used for the subsequent reaction without purification.

Production Example 5 (7R, 9aS) -7-hydroxymethyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H- [1, 2-a] pyrazine 4.41 g (18.2 mmol) of (7R, 9aS) -7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine.2HCl ( Production Example 1), 3.78 g (28.5
mmol) of 2-chloro-5-fluoropyrimidine (B. Baas
ner, E., Klauke J. Fluroine Chem., 1989, 45, 417-430)
And a 180 mL aqueous solution of 9.07 g (85.6 mmol) of sodium carbonate was heated to 95 ° C. for 16 hours. Cool the mixture to room temperature,
Extract with chloroform (2x) and (with magnesium sulfate)
Dry, pass and evaporate. Purification by flash chromatography on silica gel using 95: 5 chloroform: methanol gave 5.56 g (81%) of the title compound. mp 148-149.5 ° C. ¹³ C NMR (CDCl ₃ ): δ 26.8,
29.0,39.1,44.2,49.7,54.8,58.7,60.8,66.2,145.0,145.
3,149.9,153.2,158.7. Calcd for C ₁₃ H ₁₉ FN ₄ O:
C, 58.63; H, 7.19; N, 21.04; Found: C, 58.36; H, 7.18; N, 20.
87.

Production Example 6 (7RS, 9aSR) -7-hydroxymethyl-2,3,4,6,7,8,9,
9a-octahydro-2- (5-fluoro-4-thiomethylpyrimidin-2-yl) -1H-pyrido [1,2-a] pyrazine The title compound was prepared according to Preparation Example 5 using (7RS, 9aSR) -7-
Hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-
1H-pyrido [1,2-a] pyrazine (US Pat. No. 5,326,874)
And 2-chloro-5-fluoro-4-thiomethylpyrimidine (Uchytilova, V .; Holy, A .; Cech, D .; Gut, J. Coll. C
zech.Chem.Commun., 1975,40,2347.Ueda, T.; Fox, JJJM
ed. Chem., 1963, 6, 697) and used for subsequent reactions without purification.

Production Example 7 (7R, 9aS) -2-BOC-7- (4-fluorophenoxy) methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a ] Pyrazine 12.0 g (44.4 mmol) of (7R, 9aS) -2-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-
Pyrido [1,2-a] pyrazine (WO 93/25552), 7.47 g (6
6.7 mmol) of 4-fluorophenol, 14.0 g (53.3 mmo)
l) 8.40 mL of a 450 mL THF solution of triphenylphosphine
(53.3 mmol) of diethyl azodicarboxylate and stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate and treated with HCl (g) in ethyl ether until precipitation ceased. The solvent was evaporated and the solid residue was washed repeatedly with 1: 1 ethyl acetate: ethyl ether. The residue was dissolved in chloroform and washed with 15% NaOH. Dry the organic phase (over magnesium sulfate), filter and evaporate to 15.9 g.
Yielded yellow-white crystals of Crude product in 1: 1 hexane:
Dissolved in ethyl acetate and passed through a silica gel plug to give 13.3 g (82%) of the title compound. mp90-92
° C. ¹³ C NMR (CDCl ₃ ): δ 26.9, 28.4, 28.8, 54.8, 58.7, 6
0.8,71.6,79.7,115.33,115.44,115.58,115.89,154.6,15
5.1,155.6,158.8. Calcd for _{C 20 H 29 FN 2 O 3} : C, 6
5.91; H, 8.02; N, 7.69; Found: C, 65.90; H, 8.06; N, 7.77.

Production Example 8 (7R, 9aS) -7- (4-fluorophenoxy) methyl-
2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine 44.4 g (122 mmol) of (7R, 9aS) -2-BOC-7- (4
-Fluorophenoxy) methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (Production Example 7) in 500 mL of trifluoroacetic acid and 200 mL of water. Stirred at room temperature for 16 hours. The mixture was concentrated by evaporation, the residue was dissolved in water, basified with 15% NaOH and extracted with ethyl acetate (2x). The organic layer was dried (magnesium sulfate), filtered and evaporated to give 31.4 g (96%) of (7R, 9a
S) -7- (4-Fluorophenoxy) methyl-2,3,4,
This gave 6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine, which was suitable for use in subsequent reactions. Purification of a 0.40 g sample by flash silica gel chromatography, eluting with 90:10 chloroform: methanol, gave 0.38 g of colorless crystals. mp
(.2HCl) 200-201 ° C. ¹³ CNMR (base, CDCl ₃ ): δ2
7.2,29.1,36.3,45.9,51.9,56.0,59.1,62.5,71.7,115.4
(D, J _CF = 8), 115.7 (d, J _CF = 23). HRMS Calcd for _{C 15 H 21 FN 2 O:} 264.1638; Found: 264.1660.

Production Example 9 (7S, 9aR) -7- (4-fluorophenoxy) methyl-
2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine ・ 2HCl 0.39 g (1.4 mmol) of (7S, 9aR) -2-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-
Pyrido [1,2-a] pyrazine, 0.24 g (2.2 mmol) of 4-
0.27 mL (1.7 mmol) of a 20 mL dry THF solution of fluorophenol and 0.45 g (1.7 mmol) of triphenylphosphine
Of diethyl azodicarboxylate and stirred at ambient temperature for 16 hours. The solution was diluted with ethyl acetate and treated with excess HCl (g) in ethyl ether. The solvent was evaporated and the white solid residue was washed with 1: 1 ethyl acetate: ethyl ether. Dissolve the remaining solid in chloroform and add 1M
Wash with NaOH, dry (magnesium sulfate), filter and evaporate to give 0.45 g of (7S, 9aR) -2-BOC-7-
(4-Fluorophenoxy) methyl-2,3,4,6,7,8,9,9a
To give octahydro-1H-pyrido [1,2-a] pyrazine.

0.44 g (1.2 mmol) of (7S, 9aR) -2-BOC-7- (4
-Fluorophenoxy) methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine in 25 mL chloroform solution with excess HCl (g) in ethyl ether. Worked up and stirred at ambient temperature for 2 hours. Evaporation of the solvent gave 0.40 g of the title compound as the dihydrochloride salt, which was used for the subsequent reaction without purification.

Production Example 10 (7R, 9aR) -7- (4-Fluorophenoxy) methyl-
2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine 0.71 g (2.63 mmol) of (7R, 9aR) -2-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-
Pyrid [1,2-a] pyrazine, 0.44 g (3.94 mmol) of 4-
0.50 mL (3.16 mmol) of a 25 mL THF solution of fluorophenol and 0.83 g (3.16 mmol) of triphenylphosphine
Of diethyl azodicarboxylate and stirred at ambient temperature for 16 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with 1M NaOH (2x). The organic layer was dried (magnesium sulfate), filtered and evaporated. 75:25
Purification by flash chromatography with ethyl acetate: hexane gave 0.5 g of a sticky solid. This material was dissolved in chloroform, washed with 1 M NaOH, dried (magnesium sulfate), filtered and evaporated to give
20 g of (7R, 9aR) -2-BOC-7- (4-fluorophenoxy) methyl-2,3,4,6,7,8,9,9a-octahydro-1H-
Pyrido [1,2-a] pyrazine was provided.

0.20 g (0.55 mmol) of (7R, 9aR) -2-BOC-7- (4
-Fluorophenoxy) methyl-2,3,4,6,7,8,9,9a-Octahydro-1H-pyrido [1,2-a] pyrazine in 10 mL trifluoroacetic acid and 3 mL water at ambient temperature for 4 hours Stirred. The mixture was concentrated under reduced pressure and the residue was diluted with water. Adjust the solution to pH 12 with 15% NaOH and add ethyl acetate (2x)
Extracted. Dry the organic phase (over magnesium sulfate)
Filtered and evaporated to give 0.149 g of the title compound, which was used for the subsequent reaction without further purification.

Production Example 11 (7RS, 9aSR) -7-hydroxymethyl-2,3,4,6,7,8,9,
9a-octahydro-2- (pyridin-2-yl) -1H-
Pyrido [1,2-a] pyrazine 1.0 g (5.9 mmol) of (7RS, 9aSR) -7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (US Pat. 5,326,874), 4.6g (29
mmol) of 2-bromopyridine, 1.5 g (14 mmol) of sodium carbonate and 50 mL of isoamyl alcohol.
Refluxed for 18 hours. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium carbonate. The organic layer was dried (magnesium sulfate), filtered and evaporated, the crude product was eluted by flash chromatography on silica gel, first with chloroform, followed by 95: 5 chloroform: methanol And purified to give 0.61 g (42
%) Of the title compound. ¹³ C NMR (base, CDCl ₃ ):
δ26.8,29.0,39.0,45.1,50.7,54.8,58.7,60.8,66.0,10
7.1,113.3,137.5,147.9,159.3.

Production Example 12 3-[(7R, 9aS) -2,3,4,6,7,8,9,9a-octahydro-
1H-pyrido [1,2-a] pyrazin-7-ylmethyl] -3
H-benzoxazol-2-one 5.0 g (18.5 mmol) of (7R, 9aS) -2-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-
Pyrido [1,2-a] pyrazine (WO 93/25552) and 2.84
A solution of mL (20.4 mmol) of triethylamine in 200 mL of dry methylene chloride was cooled to 0 ° C. and treated with 1.50 mL (19.4 mmol) of methanesulfonyl chloride in 75 mL of methylene chloride. After 1 hour, the mixture was diluted with water, basified to pH 12 with 15% sodium hydroxide, the layers were separated, and the aqueous layer was extracted with methylene chloride. The combined organic phases were washed with brine, dried (over magnesium sulfate), filtered and evaporated to give 6.4 g (100%) of mesylate.

7.00 g (51.8 mmol) of 2-benzoxazolinone 180
Add 2.05 g (51.3 mmol) of sodium hydride (6 mL
(0% oil dispersion) and the mixture was stirred at 50 ° C. for 1.5 hours. The heat source was temporarily removed, 6.4 g (18 mmol) of the above mesylate in 180 mL DMF was added and the mixture was brought to 100 ° C. for 2 hours.
Heated for hours. The reaction was cooled to room temperature, diluted with water,
Acidify to pH 2 with 6M hydrochloric acid and wash with ethyl acetate (3x). The pH was adjusted to 12 with concentrated ammonium hydroxide and the aqueous phase was extracted with ethyl acetate (3x). The combined organics were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with ethyl acetate gave 3.55 g (50%) of 3-[(7R, 9aS) -2-BOC-
2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] Pyrazin-7-ylmethyl] -3H-benzoxazol-2-one.

3.1 g (8.01 mmol) of 3-[(7R, 9aS) -2-BOC-2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] A solution of pyrazin-7-ylmethyl] -3H-benzoxazol-2-one in 40 mL chloroform was stirred with excess HCl (g) in ethyl ether at ambient temperature for 2 hours. Evaporation of the solvent gave 2.3 g (100%) of the title compound 2 hydrochloric acid, which was used for the subsequent reaction without further purification.

Production Example 13 (7S, 9aS) -7-Hydroxymethyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1 , 2-a] Pyrazine 2.31 g (13.6 mmol) of (7S, 9aS) -7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (Production Example 2), 1.98 g (15.0 mmol)
Of 2-chloro-5-fluoropyrimidine (B. Baasner, E.
Klauke, J. Fluorine Chem., 1989, 45, 417), 4.32 g (40.8
(mmol) of sodium carbonate and 50 mL of water were heated at reflux for 16 hours. The mixture was cooled to room temperature and extracted with chloroform (3x). The combined organic layers were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 95: 5 chloroform: methanol afforded 2.7 g (75%) of the title compound. mp (base) 111-112 ° C. ¹³ C NMR (base, CDC
l ₃ ): δ26.5, 27.3, 34.2, 44.3, 49.8, 54.8, 58.8, 60.7, 6
8.2,145.0,145.3,149.9,153.2,158.6. HRMS Calcd for _{C 13 H 19 FN 4 O:} 266.1543; Found: 266.1530.

Production Example 14 (7S, 9aS) -7-Hydroxymethyl-2- (5-chloropyridin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1 , 2-a] Pyrazine 2.5 g (10.3 mmol) of (7S, 9aS) -7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,
2-a] Pyrazine dihydrochloride, a mixture of 7.62 g (51.5 mmol) of 2,5-dichloropyridine, 5.45 g (51.5 mmol) of sodium carbonate and 100 mL of isoamyl alcohol were heated under reflux for 72 hours. The mixture was cooled, the mixture was filtered to remove solids and the solvent was evaporated under reduced pressure. Purification by flash silica gel chromatography using 95: 5 chloroform: methanol provided 1.72 g (59%) of the title compound. mp (base) 61-62 ° C. ¹³ C NMR (base, C
DCl ₃ ): δ26.6, 27.2, 34.3, 45.4, 50.9, 54.6, 58.4, 60.5,
68.0,107.7,120.1,137.1,146.1,157.5. HRMS Calcd for _{C 14 H 20 ClN 3 O:} 281.1295; measured value; 281.1298.

Production Example 15 (7R, 9aS) -7-Hydroxymethyl-2- (5-chloropyridin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1 , 2-a] Pyrazine 1.35 g (5.56 mmol) of (7R, 9aS) -7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine.2HCl ( Production Example 1), 4.11 g (27.8
mmol) of 2,5-dichloropyridine, 2.94 g (27.8 mmol) of sodium carbonate and 60 mL of isoamyl alcohol were heated to reflux for 48 hours. The mixture was cooled and the solvent was removed under reduced pressure. Purification by flash silica gel chromatography in 95: 5 chloroform: methanol yields:
This gave 1.02 g (65%) of the title compound. mp (base) 139
~ 140.5 ° C. ¹³ C NMR (CDCl ₃ ): δ 26.8, 29.1, 39.1, 45.3,
50.8,54.6,58.6,60.6,66.2,107.7,120.1,137.1,146.2,1
57.6.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 9/04 A61P 9/04 9/12 9/12 25/00 25/00 25/16 25/16 25/18 25/18 25/20 25/20 25/30 25/30 27/02 27/02 (72) Inventor: Sanna, Mark A. Hillcrest Drive, Old Saybrook, Old Saybrook, 06475, Connecticut, U.S.A. Hei 2-233681 (JP, A) Special table Hei 5-507274 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 471/04 120 A61K 31/4985 A61K 31/506 CAPLUS (STN) REGISTRY (STN)

Claims (11)

(57) [Claims] [Claim 1] The formula: Wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl; Ar ¹ is phenyl, pyridinyl A is O; n is 0, 1 or 2; each of Ar and Ar ¹ is, independently, and optionally,, pyridazinyl, pyrimidinyl, or pyrazinyl;
Fluorine, chlorine, bromine, iodine, cyano, nitro, _{thiocyano, -SR, -SOR, -SO 2 R} , -NHSO 2 R, - (C 1 ~C 6)
Alkoxy, -NR ¹ R ² , -NRCOR ¹ , -CONR ¹ R ² , Ph, -CO
_{R, COOR, - (C 1} ~C 6) alkyl; - consisting (C ₁ ~C ₆₎ alkyl ;-( C ₃ ~C ₆₎ cycloalkyl, and trifluoromethoxy substituted with 1-6 halogens Each and every R, R ¹ and R ² may be hydrogen,-(C ₁ -C ₆ ), optionally substituted with 1-4 substituents independently selected from the group
Alkyl; fluorine, chlorine, substituted by 1 to 13 halogen selected from bromine and iodine - (C ₁ ~
C ₆₎ alkyl; phenyl, benzyl, - (C ₂ ~C ₆₎ alkenyl, - (C ₃ ~C ₆₎ cycloalkyl and - (C ₁ ~
C ₆ ) is independently selected from the group consisting of alkoxy; each and every R ³ and R ⁴ are hydrogen, methyl, ethyl,
Independently selected from the group consisting of n-propyl and i-propyl. And diastereomers and optical isomers thereof; and pharmaceutically acceptable salts thereof. 2. Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl or quinolyl; n is 0 or 1; Ar and Ar ¹ are fluorine, chlorine, cyano,- NR ¹ R ² , −
(C ₁ -C ₆ ) alkoxy, —COOR, —CONR ¹ R ² and — (C
₁ -C ₆₎ with up to three substituents independently selected from the group consisting of alkyl optionally substituted independently The compound according to claim 1 or a pharmaceutically acceptable salt thereof . 3. The compound according to claim 2, wherein n is 1; and Ar is phenyl or substituted phenyl, or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 3, wherein Ar is fluorophenyl, difluorophenyl or cyanophenyl; or Ar ¹ is chloropyridinyl, or a pharmaceutically acceptable salt thereof. 5. The method according to claim 3, wherein Ar is fluorophenyl, difluorophenyl or cyanophenyl; Ar ¹ is fluoropyrimidinyl.
Or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 3, wherein Ar is fluorophenyl, difluorophenyl or cyanophenyl; or the pharmaceutically acceptable salt thereof, wherein Ar ¹ is fluorophenyl. 7. The compound according to claim 4, wherein Ar ¹ is 5-chloro-pyridin-2-yl. 8. The method according to claim 8, wherein Ar ¹ is 5-fluoro-pyrimidine-2-
A compound according to claim 5, which is yl. (9) (7R, 9aS) -7- (4-fluorophenoxy) methyl-2- (5-chloro-pyridin-2-yl)
-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2
-A] pyrazine; (7R, 9aS) -7- (3,5-difluorophenoxy) methyl-2- (5-chloro-pyridin-2-yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7R, 9aS) -7- (4-fluorophenoxy) methyl-
2- (5-fluoro-pyrimidin-2-yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7R, 9aS) -7- (3,5-difluorophenoxy) methyl-2- (5-fluoro-pyrimidine -2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine; (7R, 9aS) -7- (3,4-difluorophenoxy) methyl-2- (5-fluoro-pyrimidin-2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine; (7R, 9aS) -7- (3-cyanophenoxy) methyl-2
-(5-fluoro-pyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7R, 9aS) -7- (4-cyanophenoxy) methyl-2
-(5-fluoro-pyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7R, 9aS) -7- (4-iodophenoxy) methyl-2
-(5-fluoro-pyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7R, 9aS) -7- (4-fluorophenoxy) methyl-
2- (4-fluorophenyl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (4- Fluorophenoxy) methyl-
2- (5-fluoro-pyrimidin-2-yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (2-carbomethoxy-4-fluorophenoxy) methyl-2- (5- Fluoro-pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-
Pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (2-bromo-4-fluorophenoxy) methyl-2- (5-fluoro-pyrimidin-2-yl) -2,3,4, 6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (4-fluoro-2-trifluoromethylphenoxy) methyl-2- (5 -Fluoro-pyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-
1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (3,5-difluorophenoxy) methyl-2- (5-chloro-pyridin-2-yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (4-fluorophenoxy) methyl-
2- (5-chloro-pyridin-2-yl) -2,3,4,6,7,
8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (4-fluoro-2-methylphenoxy) methyl-2- (5-fluoro-pyrimidine-2 -Yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (2,4-difluorophenoxy) Methyl-2- (5-fluoro-pyrimidin-2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine; (7S, 9aS) -7- (3-methyl-phenoxy) methyl-
2- (5-fluoro-pyrimidin-2-yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (3,4-difluorophenoxy) methyl-2- (5-fluoro-pyrimidine -2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine; (7S, 9aS) -7- (3,5-difluoro-phenoxy) methyl-2- (5-fluoropyrimidin-2-yl) -2,
3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-
a] pyrazine; (7S, 9aS) -7- (3-cyano-phenoxy) methyl-
2- (5-fluoropyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (3-trifluoromethyl-phenoxy) methyl-2- (5-fluoropyrimidine-2 -Yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (4-trifluoromethyl-phenoxy) ) Methyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS ) -7- (3-Trifluoromethoxy-phenoxy) methyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [ (7,9aS) -7- (3-methoxy-phenoxy) methyl-2- (5-fluoropyrimidin-2-yl) -2,3,4,
6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7S, 9aS) -7- (4-methoxy-phenoxy) methyl-2- (5-fluoropyrimidine-2 -Yl) -2,3,4,
6. The compound according to claim 1, wherein the compound is selected from the group consisting of 6,7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; and a pharmaceutically acceptable compound thereof. salts. 10. A compound represented by the formula: [Wherein, Ar ¹ is 5-fluoropyrimidin-2-yl or 5-chloropyridin-2-yl, and Ar is 4-fluorophenyl. And the stereoisomers, optical isomers and salts thereof. (11) (7R, 9aS) -7-hydroxymethyl-2
-(5-fluoro-pyrimidin-2-yl) -2,3,4,6,
7,8,9,9a-octahydro-1H-pyrido [1,2-a] pyrazine; (7R, 9aS) -7- (4-fluoro-phenoxy) methyl-2,3,4,6,7,8 , 9,9a-Octahydro-1H-pyrido [1,2
-A] pyrazine; (7S, 9aS) -7-hydroxymethyl-2- (5-chloro-pyridin-2-yl) -2,3,4,6,7,8,9,9a-octahydro-1H- Pyrido [1,2-a] pyrazine; (7R, 9aS) -7-hydroxymethyl-2- (5-chloropyridin-2-yl) -2,3,4,6,7,8,9,9a- Octahydro-1H-pyrido [1,2-a] pyrazine; and (7S, 9aS) -7-hydroxymethyl-2- (5-fluoro-pyrimidin-2-yl) -2,3,4,6,7 11. The compound according to claim 10, wherein the compound is selected from the group consisting of: 8,8,9a-octahydro-1H-pyrido [1,2-a] pyrazine.